research grants council theme-based research … · hc-specific removal of both . irx3. and . irx5....
TRANSCRIPT
TRS6 (01/18)
RESEARCH GRANTS COUNCIL
THEME-BASED RESEARCH SCHEME (TRS)
Completion Report on Funded Project
Project start date: 1/1/2013
Project completion date: 31/12/2018
1. Project Title: Functional analyses of how genomic variation affects personal risk for
degenerative skeletal disorders
2. Names and Academic Affiliations of Project Team Members#
Project team
member Name / Post
Unit / Department /
Institution
Average number
of hours per week
spent on this
project in the
whole project
period
Project
Coordinator (PC) Cheah, Kathryn SE
/Chair Professor School of Biomedical
Sciences##, HKU 11 hours
Co-Principal
Investigator(s)
Chan, Barbara
/Asso. Professor^^ Mechanical Engineering HKU 9 hours
Chan, Danny/
Professor School of Biomedical
Sciences##, HKU 9 hours
Cheah, Kathryn SE
/Chair Professor School of Biomedical
Sciences##, HKU 11 hours
Cheung, Kenneth
MC/Professor
Orthopaedics & Traumatology
(O&T), HKU 4.5 hours
Jin, Dong Yan/
Professor
School of Biomedical
Sciences##, HKU 4.5 hours
Project number:T12-708/12N
Lam, Yun Wah
/Asso. Professor Biology & Chemistry, City U 9 hours
Lian, Qizhou$
/Asst. Professor Medicine, HKU 9 hours
Luk, Keith DK/ Chair
Professor O&T, HKU 4.5 hours
Sham, Pak
/Chair Professor
Psychiatry/Genomic Centre
HKU 4.5 hours
Zhang, Michael
/Chair Professor
Psychiatry/School of
Biomedical Sciences##,
HKU& UT Dallas USA
2 hours
TRS6 (01/18)
Co-Investigator(s)
Cherny, Stacey$
/Asst. Professor Psychiatry, HKU 1.5 hours
Huang, Jian Dong
/Professor School of Biomedical
Sciences##, HKU 2 hours
Ng, Ray
/Asst. Professor School of Biomedical
Sciences##*, HKU 2 hours
Samartzis, Dino$
/Asst. Professor O&T, HKU 4.5 hours
Song, Y.Q.
/Asso. Professor
School of Biomedical
Sciences##, HKU 2 hours
Wang, Junwen^
/Asst. Professor
Centre for Genomic Science,
HKU 2 hours
Collaborators
Ikegawa, S.
/Laboratory Head Center for genomic Medicine
RIKEN, Japan N.A.
Karpinnen, J.
/Professor
Physical Medicine and
Rehabilitation, Univ. of Oulu,
Finland N.A.
Liu, P./Senior Group
Leader
Wellcome Trust Sanger
Institute, Cambridge, UK** N.A
Mannikko, M.
/Adjunct Professor
Institute of Biomedicine, Univ.
of Oulu, Finland N.A
Rajasekaran, S.
/Chairman
Dept of Orthopaedics & Spine
Surgery Ganga Medical Centre
& Hospitals, India
N.A
Zeggini, E.
/Group Leader
Wellcome Trust Sanger
Institute, Cambridge, UK N.A
Faessler, R & Mann, M/
Professors & Directors
Max Planck Inst Martinsreid,
Germany N.A
Overall, C./
Professor, Canada
Dept. Oral Biological &
Medical Sciences, Univ.
British Columbia, Canada
N.A
Stupp, S./Professor &
Director
Inst. BioNanotechnology in
Medicine, Northwestern
University, USA N.A
#Nieto, A. /Professor &
Head of Dept.
Instituto de Neurociencias
CSIC-UMH
N.A
# Please highlight the approved changes in the project team composition and quote the date when
the RGC granted approval of such changes. For changes in the project team composition, please
submit a separate request, together with the justification and the curriculum vitae of the new member(s), to the RGC three months prior to the intended effective date of the change. ^^ Currently Professor
*Formerly affiliated with Dept. of Pathology, HKU
** Currently Professor of School of Biomedical Sciences, HKU
## Formerly Biochemistry, HKU
^left HKU and the team on 15 April 2016. His share of work has been taken up fully by Prof Pak
Sham and Prof. Michael Zhang and a new postdoctoral fellow.
$left HKU recently and continue their support on the project. Latest affiliations are as follow:1. Dr Qizhou Lian: Scientific Officer and Manager, HKUMed GMP laboratory of AdvancedCellular Therapeutics LKS faculty of Medicine, HKU (Effective Date: February 2019)2. Dr. Stacey Cherny: Senior Researcher - Epidemiology and Preventive Medicine, Tel AvivUniversity, Israel. (Effective Date: September 2017)3. Dr. Dino Samartzis: Associate Professor, Department of Orthopaedic Surgery RushUniversity, Chicago, USA (Effective Date: January 2018)
TRS6 (01/18)
3. Project Objectives
Summary of objectives addressed/achieved:
Objectives* Percentage
achieved Remarks**
1. To understand the
molecular pathology
and progression of
disc degeneration
100% Insights into IVD development and degeneration gained from
mouse mutants and mouse models for IDD (ER stress model;
disc compression via tail looping; poor healer
mice) established; transcriptome data on developing/postnatal
mouse nucleus pulposus (NP). Elucidated molecular
mechanism for impact of cellular/ER stress on hypertrophic
chondrocyte (HC) differentiation and cell survival; roles of
cell-cell and cell-matrix interactions; cell-cycle regulation;
contribution of HCs to inner annulus fibrosus and their
potential role in IVD recovery from compression injury.
Mouse IDD scoring system published.
TGFβ, stress pathway, N-cadherin, β1 integrin implicated in
mouse IVD development and IDD. Developmental profile of
mouse notochord and NP cells RNAome. Molecular
signatures (RNAome) of constituent populations of human
NP, definition of notochordal-like (NCL) and chondrocyte-
like (CLC) cells in non degenerated NP, and of populations in
degenerated NP. Evidence for transformation of NCL to CLC
to fibroblasts in injury-induced IDD.
Comparative analyses of transcriptomes of human
degenerated and non-degenerated NP at single cell resolution
reveal massive changes in cell populations, evidence for
transformation of NCLs to CLCs and fibroblasts; cytokine-
cytokine receptor, TGFβ pathway, cell-matrix interactions and
inflammatory pathways and mineralisation implicated;
integrated stress response and partial EMT process implicated
as early in etiology, culminating in fibrosis and IDD. HOPX
identified as a master regulator for maintaining NCL identity.
Produced deep proteome of mouse IVD in lumbar and tail
regions; reference spatial proteome of human lumbar discs in
young (healthy) and aged (degenerated) individuals.
Comparative SILAC proteome of human IVD samples, in
relation to the secretome and degradome. Towards therapy:
showed small molecule inhibition of the ISR and chemical
chaperone alleviates growth plate and osteoblast
differentiation defects caused by ER stress, with exciting implications for the treatment of congenital dwarfism/bone overgrowth associated with cellular stress. Two patent applications filed. Papers published, media coverage.
TRS6 (01/18)
2. To correlate IDD
severity and
progression with
genetic variations
100% Follow-up MRI finished. Improved IDD phenotyping and
classification; UTE-MRI publications. Characterized
longitudinal progression of IDD sub-phenotypes over time
from loss of signal intensity or disc bulging to other changes,
and from one level to the next; Combined analysis of genomic
and metabolomics data indicating influence of blood lipid
related genetic variants on lumbar modic changes, suggesting
the interplay of local and systemic factors in IDD progression.
Papers in preparation.
3. To discover the
functional
implications of
genomic risk loci.
100% Novel risk factors identified from genomic and genetic studies
in SMJ and LGJ mice. Mouse models for IVD implicated
aberrant TGFb signaling caused by over-expression of ASPN,
a genetic risk factor, via disruption of fibrillin network leading
to chondrogenic and fibrotic events. Papers published.
4. To identify key
intrinsic and extrinsic
niche factors for the
differentiation of disc
cells from pluripotent
stem cells and for
their maintenance
100% Mouse: Integrated transcriptome and epigenetic data revealed
dynamic shift in pathway prominence from notochord to NP.
Single cell RNAseq (scRNAseq) revealed cell transition states
and heterogeneity in HC-to-osteoblast transition. Validated
similarity of chordoma cells to notochordal-like cells NCLs.
Identified potential stem cell/progenitors in mouse IVD.
Showed HOPX is master factor for maintaining NCL identity.
Papers in preparation.
5. To develop a cellular
platform for
maintaining disc cells
and for tests of disc
cell function
100% Ex vivo system recapitulated notochord to NP transition for
functional studies. 3D segment culture and tube co-culture
demonstrated the significance of niche cells in phenotype
maintenance of NCCs in notochord. 3D culture systems
incorporated with proteoglycan, collagen and laminin support
in vitro maintenance of NPCs. Directed differentiation of
NCCs and NP-like cells from human and mouse ES cells.
Papers published, one in revision, another in preparation.
6. To integrate clinical
profile, phenotype,
genomic and
functional data for
prediction of risk for
developing IDD and
back pain
100% Sub-phenotype classification of spine disc MRI images and
utilization for genetic studies. Evidence for developmental and
degenerative etiologies for IDD. Exome sequencing of 715
individuals completed.
IDD genetically correlated with bone mineral density and body
mass index in cross-disorder polygenic regression analysis
published. TGFβ, integrin pathway and new candidate genes
implicated in variant-based, gene-based and pathway set-based
association analyses. Papers published, several others in
preparation.
* Please highlight the approved changes in objectives and quote the date when the RGC
granted approval of such changes.
** Please provide reasons for significantly slower rate of progress than originally planned.
TRS6 (01/18)
6. Research Highlights and Outputs
6.1 What are the most exciting research accomplishments of the project?
The following discoveries break new ground on gene function and regulation in skeletal development
and the molecular pathogenesis and genetics of skeletal disorders.
A. REGULATION OF SPINE DEVELOPMENT, GROWTH IN HEALTH AND IDD
A1. Genetic control of chondrocyte differentiation in endochondral bone formation
Cartilage and endochondral bone formation and growth depend on a finely controlled cascade of
differentiation steps involving proliferation, cell cycle exit, maturation and hypertrophy. By integrating
the transcriptomes of growth plate chondrocyte populations from mice carrying different mutations,
we discovered a SOX9-GLI-FOXA phasic gene regulatory network in chondrocyte differentiation,
which provides important insights into normal chondrocyte differentiation and the molecular
consequences of perturbation, with relevance to the pathogenesis of chondrodysplasia. SOX9-GLI
auto-regulate and cooperate to activate and repress genes in proliferating chondrocytes. Upon
hypertrophy, FOXA competes with SOX9, and control of terminal differentiation passes to FOXA,
RUNX, AP1 and MEF2.
Outcome and esteem indicators: Publication
Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network
coordinate chondrocyte differentiation transitions. PLoS Genet. 14(4):e1007346 (2018), citations,
5. (#101)
Conference abstracts: Presented at Gordon Research Seminar and Gordon Research Conference
on Cartilage Biology and Pathology 2017. (#59 and #60)
Awards: Best Poster Presentation to postdoc fellow "Synergistic co-regulation and competition
underlies a SOX9-GLI- FOXA phasic transcriptional network that coordinates growth plate
chondrocyte differentiation " in both Gordon Research Seminar and Gordon Research
Conference (Cartilage Biology and Pathology) April 1 - 2, 2017 Lucca (Barga), Italy.
Web resource: GP-DGEL (www.sbms.hku.hk/kclab/gp.php); visited 3377 times (26/12/2019).
Collaborations: A. McMahon (University of Southern California, USA) and M. Zhang
(University of Texas at Dallas, USA).
A2. Mechanism of chondrocyte to osteoblast transdifferentiation
Osteoblasts in trabecular bone are derived from perichondral osteoprogenitors, which accompany
vascularisation of the primary spongiosa, and mesenchymal stem cells. We published a landmark paper
in 2014 showing that the lineage of chondrocytes and osteoblasts is a continuum in which hypertrophic
chondrocytes (HCs) become osteoblasts and osteocytes (Hc-Ob lineage). This discovery, highlighted
by Faculty of 1000, confirmed by others, overturned dogma on the origin of bone cells and attracted
international attention and citations (227). In the TRS programme, we used mouse genetics and
transcriptomics to dissect the mechanisms and regulatory pathways that control HCs transformation
into osteoblasts. By sequencing single cells, we found that HCs first enter a transition state in which
transcription factors of the epithelial-to-mesenchymal transition (EMT) pathway (Snail/Twist1/2,
Zeb1) and the E2F family of proliferation regulators are activated. The cells then renter the cell cycle
and enter a mesenchymal state, before differentiating to become osteoprogenitors, pre-osteoblasts and
osteoblasts. Interestingly, 2.5% of the HC descendant cells expressed adipogenic transcription factors
(e.g. Pparg and Cebpa), suggesting that they can become adipocytes. The findings reveal the plasticity
of HCs which can “reprogram” to become mesenchymal-like bi-potential progenitors that produce
osteoblasts and, to a lesser extent, adipocytes. By studying conditional HC-specific mutants in which
specific transcription factors were removed using a HC-specific Cre, we found Sox9, Irx3, Irx5, and β-
catenin play key roles in regulating the HC-to-osteoblast transition.
β-catenin and Irx3/5 deficiency in HC descendants increases bone marrow adiposity β-catenin is the canonical Wnt signaling mediator encoded by the gene Ctnnb1 and is critical in
TRS6 (01/18)
promoting osteoblastogenesis and bone formation. We showed that conditional loss-of-function (LOF)
mutations in Ctnnb1 in the HC lineage dramatically reduced the amount of trabecular bone, whereas
gain-of-function (GOF) mutations that constitutively stabilize β-catenin increased bone mass. We
found osteoblast markers were upregulated in GOF mutants compared with wild-type, and
downregulated in LOF mutants, consistent with impaired osteoblast differentiation. In the LOF
mutants, we also found concomitant and striking up-regulation of genes associated with adipogenesis
and marked increase in bone marrow adiposity contributed by the HC descendants, indicating
preferential commitment towards adipocyte differentiation, a process regulated by the master
transcription factor PPARγ.
The transcription factors Irx3 and Irx5 may mediate WNT signaling in chondrocyte fate
determination. We found Irx3 null mice have increased number of marrow adipocytes, suggesting a
role for this transcription factor in controlling adipogenesis. HC-specific removal of both Irx3 and Irx5
results in fewer HC-derived osteoblasts and more (in both number and proportion) HC-derived
adipocytes, indicating that Irx3 and Irx5 are also important regulators of osteoblast differentiation and
commitment of HC to the osteoblastic lineage. Our study provides molecular understanding of the gene
regulatory network governing the balance between adipogenesis and osteogenesis of HC-derived
progenitors, and the pathological bases of many disorders, including osteoporosis and obesity. These
important questions are being addressed in a GRF project supported in 2017.
We also found an unexpected systemic impact of the altered bone marrow fat-bone homeostasis
in Ctnnb1 LOF mutants, which have lower body fat and higher lean mass and better glucose tolerance
compared to controls. These findings open up a new research direction to address the specific function
of bone marrow fat, where we can induce HC-specific mutations to investigate how modulating bone
marrow adipogenesis separately from peripheral fat may alter body composition, glucose tolerance and
insulin sensitivity. This is enabling us to test the hypothesis that bone marrow adipose tissue has
specific roles when challenged with a high fat diet, with support from a new HMRF grant awarded in
2019.
MMP14 cleaves PTH1R, regulating the contribution of the chondrocyte-osteoblast lineage to
bone
The relative contribution of HC-derived osteoblasts to total endochondral bone is unknown. Treating
mice with the PTH(1-34) peptide increases trabecular bone by inhibiting apoptosis and enhancing
signalling through Pth1r. We found that the HC-Ob lineage made a significant contribution to the
additional bone induced by PTH (1-34). Matrix metalloproteinases (MMPs) are active at the chondro-
osseous junction of the growth plate, degrading hypertrophic cartilage and releasing HCs, and could
be regulators of the HC-to-osteoblast transition. We identified the membrane-bound metalloproteinase,
MMP14, as a candidate regulator, since it is not expressed in HCs but is strongly expressed just beneath
the chondro-osseous junction. Mice lacking MMP14 display many abnormalities, including reduced
bone mass associated with enhanced osteoclast activity. We used a HC-specific Cre to inactivate
Mmp14 in HC-descendants, which unexpectedly resulted in an increase in the number of HC-derived
cells and amount of trabecular bone. Treating Mmp14 ΔHC mice with the PTH(1-34) peptide caused a
dramatic expansion of the HC-Ob lineage and increased trabecular bone. In Mmp14ΔHC mutants,
PTH1R remains uncleaved and thus active, leading to increased osteoblasts and bone synthesis. We
found MMP14 directly cleaves the extracellular domain of PTH1R thereby modulating signaling
activity, identifying MMP14 as a novel protease for PTH1R, controlling the supply of chondrocyte-
derived osteoblasts. An application for HMRF support for defining the physiological role of MMP14
control of HC-derived osteoblasts in maintaining bone mass during life-span is approved subject to
clarifications.
Outcome and esteem indicators
Publications in preparation
o Transition states and beta catenin control of lineage trajectories in chondrocyte to osteoblast
transdifferentiation. Target journal eLife/Developmental Cell (#155)
o MMP14 cleaves PTH1R, regulating the contribution of the chondrocyte-osteoblast lineage
continuum to bone. Target journal Nature Cell Biology/J Clinical Investigation (#156)
o IRX3 and IRX5 inhibit adipogenic differentiation of hypertrophic chondrocytes and promote
osteogenesis. Target journal J Clinical Investigation.(#157)
TRS6 (01/18)
● Award: Best Oral Presentation “MMP14 Regulates Lineage Progression of Hypertrophic
Chondrocyte” 21st Research Postgraduate Symposium, Li Ka Shing Faculty of Medicine, The
University of Hong Kong, December 10 & 11, 2016
● Invited reviews:
o Fate of growth plate hypertrophic chondrocytes: Death or lineage extension? Development,
Growth & Differentiation. 57:179-192 (2015). (#52)
o Wiley Blackwell Prize 2016 for The Most Downloaded Paper among those published in
Development, Growth & Differentiation volume 57
o Mechanistic insights into skeletal development gained from genetic disorders. Current Opinion
in Genetics & Development 133:343-385 (2019).(#115)
o The extended chondrocyte lineage: implications for skeletal homeostasis and disorders. Current
Opinion in Cell Biology 61:132-140 (2019).| (#116)
o Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease. J Orthop Res
2019 doi: 10.1002/jor.24523. (#112)
● Invited lectures at international conferences: 8 invited talks, highlights:
o “Rewriting concepts on the ontogeny of bone cells” 17th International Congress of Developmental
Biology, Cancun, Mexico, June 16-20, 2013. (#36)
o “Genetic control of hypertrophic chondrocyte to osteoblast differentiation in development
and skeletal disorders” American Association of Anatomists (AAA) 2016 Annual Meeting, San
Diego, USA, April 2-5, 2016. (#48)
o “Chondrocyte Plasticity and Fate Determination in Development and Disease” Gordon Research
Conference on Cartilage Biology & Pathology, Lucca (Barga), Italy, April 2-7, 2017. (#56)
o “Skeletal lineage plasticity in development and disease“ Orthopaedic Research Society 2019
Annual Meeting, Austin, TX, USA, February 2-5, 2019. (#66)
● Grants
o 2017 GRF project “Molecular control of hypertrophic chondrocyte cell fate and lineage
extension”. HK$1.2M
o 2019 HMRF project “The role of bone marrow adipose tissue in glucose tolerance and insulin
sensitivity”. HK$1.5M (awarded to TRS postdoc fellow Dr. K.Y. Tsang)
● PhD awards. 2 in 2018, “MMP14 and Regulation of Hypertrophic Chondrocyte to Osteoblast
Lineage”; “Roles of Irx3 and Irx5 in Skeletal Cell Lineage Determination”.
A3. Insights into the development, maturation and aging of the IVD
Lineage origin of nucleus pulposus (NP) precursors, The notochord is the major embryonic skeletal element driving longitudinal growth, producing signals
that are critical for induction and patterning of the sclerotome, which gives rise to the vertebral body.
We and others have shown by developmental lineage studies in mice that NP cells are derived from a
common precursor in the embryonic notochord. We developed mice in which notochordal cell (NCC)-
specific expression of Cre recombinase is driven by a notochord-specific enhancer from the Foxa2
gene (Foxa2-MNE). Crossing Foxa2-MNE-Cre mice to those carrying a Cre reporter (Z/EG) activates
expression of GFP in NCCs which persists in NCC descendants, thereby providing information on
lineage origin. Our lineage tracing studies in these mice showed fetal, postnatal and adult nucleus
pulposus (NP) cells are derived from the notochord (paper submitted). These mice have provided an
important resource for the study of NCCs/NPCs, for lineage-directed differentiation of mouse
embryonic stem cells (ESCs) to NCC derivatives and for functional studies on pathogenetic
mechanisms in IDD (see Section C).
New discoveries on cell-matrix interactions in NP development with disease implications Convergent extension, driven by the non-canonical Wnt/PCP (planar cell polarity) signaling pathway,
is crucial for numerous developmental processes, but it is unclear how it influences notochord
development. We showed that genetic ablation of β1 integrin, a critical cell-matrix adhesion molecule,
specifically in the notochord of mouse embryos from E8.0 onwards, impaired convergent extension of
the notochord with a reduced length:width ratio likely caused by defective directional migration of
notochordal cells. This resulted in abnormal spine development at birth, with mis-aligned vertebral
bodies, hemi-vertebrae and truncated tails. These abnormalities correlate with developmental defects
TRS6 (01/18)
manifested from early somite stages as discontinuities in the notochord, which are subsequently
displaced from the midline axes. We found treatment of wild-type embryos with β1 integrin-specific
functional blocking antibodies at E7.25, before the establishment of PCP in the node, disrupts polarized
localization of the core PCP component, Vangl2. Our study implicates cell-matrix interactions
mediated by integrin β1 in controlling PCP-mediated convergent extension of the developing
notochord. This control is crucial for the proper alignment of vertebral bodies and the intervertebral
discs and for the function of the NP.
By profiling the RNAome of the developing mouse notochord and NP at various stages from
embryonic to 8 weeks postnatal, we showed the cell adhesion molecule N-cadherin (Cdh2) is highly
expressed in notochordal-like cells (NCLs) relative to chondrocytes. Previous study had indicated a
role of Cdh2 in maintenance of NP cell phenotype in vitro. We found that notochord-specific Cdh2
heterozygous mutants (NC-Cdh2+/-) developed a fibrocartilaginous NP containing cell clusters in the
adult lumbar discs with upregulation of collagen I and II, as well as both proliferative and apoptotic
activity, a phenotype resembling degenerative human discs. Only mild changes were observed in
coccygeal levels. Tail looping in the NC-Cdh2+/- mutants led to increased incidence and severity of
degenerative changes in the coccygeal discs compared to controls. We hypothesized that discs with
decreased Cdh2 expression are more susceptible to degeneration and remodeling under mechanical
stress. Using JHC7 chordoma cells as a model, we found that CDH2-deficient cells expressed
chondrogenic genes more strongly in response to mechanical loading than control cells. This suggests
NCL transformation and hence disc maturation/degeneration depend on an interplay between genetic
and environmental factors.
Outcome and esteem indicators
Publications in preparation
o β1 integrin regulates convergent extension in mouse notogenesis. Target journal Development
(#126)
o N-cadherin modulates mechanosensensing and notochordal cell fate. Target journal PNAS (#124)
PhD award: 2018 “Role of Cadherin 2 in intervertebral disc maturation”
Collaborations: J. Hoyland (University of Manchester, UK), L. Setton (Washington University
in St. Louis, USA)
A4. Identifying potential progenitors/stem NP cells
A likely cause of disease in IDD is impairment of the reparative capacity of the intervertebral disc
(IVD) tissues. Skeletal progenitors exist in the IVD but knowledge of the heterogeneity, lineage
origins, molecular characteristics and function of these cells in maintaining a healthy disc is limited.
After birth, the NP contains many large vacuolated NCLs but these disappear rapidly with age and few
remain during adolescence. In adult IVD, the predominant cell type is smaller dispersed chondrocyte-
like cells (CLCs). The reduction of NCLs and appearance of myofibroblast-like cells in human NP
coincides with the age-onset of IDD. In contrast, NCLs persist in animals that are more resistant to
IDD, such as the mouse. We hypothesised that NCLs represent a pool of resident NPC progenitors or
quiescent cells that maintain NP function and homeostasis and need to be activated to replace senescent
cells to protect against IDD.
We found considerable cell heterogeneity in the adult mouse NP, with both long-lived “stem”
cells (slow cycling) and rapidly dividing (fast cycling) cells. We detected infrequently dividing cells
(label-retaining cells) by pulse and chase retention analysis in transgenic mice expressing a
doxycycline (DOX)-inducible H2B-GFP label, in which dilution of H2B-GFP with cell division is an
indicator of the speed of cell division. By single cell RNA sequencing, we identified a population of
NP cells enriched for expression of “stem-like” cell markers and with reduced expression of
differentiation markers, which may be a progenitor-like population of the NP important for maintaining
disc homeostasis. The sub-population of label-retaining cells, characterised by expression of Hes1,
may represent a distinct sub-group of proliferating cells which could be NP progenitors. These findings
are being followed up in a GRF project awarded in 2019.
TAGLN-expressing cells mark NCLs in healthy NP and are of notochordal origin
TRS6 (01/18)
Transgelin (TAGLN/SM22α) is expressed in NP from the human fetus at 6-14 weeks and at 10 years
but less so at 15 years. We found no TAGLN-expressing cells in severely degenerated NP from 40-
year and 46-year individuals. TAGLN is therefore a candidate marker of a healthy NP. We used mice
in which the bacterial lacZ reporter gene was inserted into the Tagln initiation codon (TaglnLacZ) to
track the expression and fate of Tagln-expressing cells in vivo. Tagln-lacZ was not expressed in the
early notochord (E11.5), but was seen in some NCC cells at E13.5. At E18.5 and P5, Tagln-lacZ was
expressed in cells in the periphery of the NP, which also expressed aSMA and Opn, and higher levels
of Sox9 and Acan than the NP core. We designated these PeriNP cells and found they are a sub-
population of NCC descendants derived from the notochord. Lineage tracing of PeriNP Tagln+ cells
labelled at fetal (E14.5, E17.5), neonatal (P4) and adult (P27) stages showed they contributed to many
cells throughout the NP. PeriNP cells may be a novel sub-population of NCC-derived progenitors in
the peripheral NP, which contribute to the growth and maintenance of the NP. Follow-up on these
exciting findings is supported by a HMRF grant in 2019.
HOPX maintains notochordal-like progenitor cell identity of human nucleus pulposus cells By screening our RNAome data from the developing mouse notochord, single cell RNA seq (scRNA)
data of 7000 cells from E12.5 tail and additional public information, we identified Hopx, encoding a
non-DNA binding homeodomain protein, as characteristic of NCC derivatives from E12.5 onwards.
We showed this NP-characteristic expression is conserved between human and mouse but that HOPX
is not expressed in human NP cells from degenerated discs.
Hopx/HOPX is important for specification of mesodermal lineages, in haematopoiesis and
specification of cardiomyoblasts, regulation of cardiomyocyte hypertrophy and maturation, and other
processes, but its role in notochordal and NP development is unknown. By loss and gain of function
experiments on HOPX in chordoma cells, we found it was essential for maintaining the characteristic
vacuolated property and molecular signature of NCLs. Loss of HOPX resulted in a fibroblastic
phenotype and expression of fibroblast markers. Lentiviral-mediated over-expression of HOPX in
primary fibroblastic cells isolated from degenerated NP resulted in the acquisition of a vacuolated
phenotype and expression of T. Therefore HOPX may be a master regulator of differentiation and/or
maintenance of the NCLs in the NP. We developed a lineage tracing system to follow the fate of
HOPX-expressing primary NP cells enzymatically harvested from NP tissues. Upon loss of HOPX
expression, HOPX descendants survived and expressed key markers characteristic of CLCs and
fibroblasts, suggesting that, like the mouse, human NCLs can give rise to CLCs and fibroblasts. The
key role of HOPX in maintaining NCL character is further illustrated by increased expression of genes
characteristic of NCLs when HOPX is overexpressed in degenerated NP cells.
Outcome
o Publication in preparation: HOPX maintains notochordal-like progenitor cell identity of
human nucleus pulposus cells. Target journal Nature Medicine.(#154)
o Conference abstracts: Presented work at SBMS Research Day, School of Biomedical
Sciences, The University of Hong Kong. 2018. (#21)
o Grants
o HMRF grant 2019 Role(s) of TAGLN expressing cells in intervertebral disc development,
homeostasis and degeneration. HK$1.5M
o GRF 2019 Analyses of progenitors and differentiation trajectories in the nucleus pulposus and
their relevance in intervertebral disc degeneration. HK$ 1.5M
o A CRF application “Functional and systems analyses of regulatory networks controlling cell fate
and lineage development of intervertebral disc cells” is under consideration.
PhD awards: 2018 “Investigation of fibrosis and myofibroblastic activity in intervertebral
disc degeneration”; 2019 “Molecular insights into human intervertebral disc degeneration
by single-cell RNA sequencing”
Collaborations: J. Hoyland, S. Richardson (University of Manchester, UK); D. Sakai (Tokai
University, Japan)
B. MECHANISMS OF IDD
We have made broken new ground in identifying progenitors in the disc, the molecular features and
TRS6 (01/18)
signatures of heterogenous cell populations in the disc in health and disease with insights into cellular
transformation in IDD. We gain new insights into the genetics of IDD and implicate association with
other disorders.
B1. NCLs can transform to become myofibroblasts in induced disc degeneration
The loss of mechanical function in IDD is associated with transformation of the extracellular matrix
(ECM) of the NP of the disc from being proteoglycan rich and hydrated, to fibrocartilaginous matrix
rich in collagens I and II, to a fibrotic state expressing collagens I and III and osteopontin. In IDD, the
NP has few cells and those present are fibroblastic, consistent with the fibrotic state. A recent study
reported that the CLCs that appear in aged mice are early NP cell descendants. However, the lineage
relationship between NCLs, CLCs and the fibroblastic cells in the degenerated NP remains unknown.
We induced IDD by annulus injury in our notochord-specific Cre (Foxa2-MNE-Cre) mice and showed
that the NP cells express GFP, indicating their notochordal origin. Soon after injury, the notochordal
descendant cells express the chondrocyte transcript Col2a1, then later the fibroblast transcript Col1a1.
We found a progressive increase in numbers of notochordal descendant cells that expressed FSP1,
FAPa and aSMA, characteristic of a fibroblastic/myofibroblastic identity. To our knowledge, this is
the first report that notochord-derived cells can transform in vivo to become fibroblastic/
myofibroblastic cells in IDD induced by injury. This finding challenges the common belief that IDD
involves cell infiltration from the endplate or annulus that remodels the NP. It opens possibilities for
modification of the response of NP cells during degeneration, with treatment potential for IDD.
Outcome and esteem indicators
Publication in preparation
o Transformation of resident notochord-descendent nucleus pulposus cells in mouse injury-induced
fibrotic intervertebral discs. Submitted to Aging Cell (#117)
o Invited lectures at international conferences
o “Fibrotic components in vertebral joint degeneration”. 4th National Conference of Chinese
Society of Matrix Biology, Changzhou, China, 2019. (#105)
o “Fibrotic components in intervertebral disc degeneration”. Bio-Spine Asia Pacific, Seoul, Korea,
2018 (#104)
Grants
o 2014 NSFC “Investigating the contribution of myofibroblast activity in intervertebral disc
fibrosis and its implication to disc degeneration mechanism”, RMB700,000
o 2018 GRF “Degraded biglycan products as fibrosis regulator in the pathomechanism of joint
degeneration” HK$814,907
PhD Award : 2018 “Investigation of fibrosis and myofibroblastic activity in intervertebral
disc degeneration”
Collaborations: Angela Nieto (Instituto de Neurociencias, CSIC-UMH, Spain)
B2. Mechanisms of IDD revealed by functional genetic studies in mouse models There are numerous strains of mice with extreme phenotypic outcomes suitable for mapping of
disease/protective traits. SM/J and LG/J mice are considered to be poor and good tissue healers,
respectively. We provided evidence of early-onset disc degeneration in the SM/J strain with
degenerative changes quantified using a histological score that we have established. We showed LG/J
mice maintain high numbers of NCLs in NP as a potential protective trait against disc degeneration. In
contrast, chondrogenic events are observed in SM/J mice beginning as early as one-week-old, with
progressive fibrotic changes and ECM changes in the NP consistent with IVD degeneration.
Leveraging the genomic data of two parental and two recombinant inbred lines between SM/J and LG/J
mice, we assessed the genetic contribution to the NP changes and identified processes linked to the
regulation of ion transport systems. Significantly, “transport” system is also in the top three gene
ontology terms from a comparative proteomic analysis of the NP of SM/J mice. An association was
shown for an equivalent ion transport gene set in our human IDD cohort. The SM/J, LG/J and
recombinant inbreds are valuable resources for future genetic and biological studies.
We generated a transgenic mouse model expressing the human Asporin (ASPN) gene, a genetic
risk factor that we previously identified in our human cohort. The changes in the IVD in these mice
TRS6 (01/18)
resemble the early-onset cellular and histological changes in SM/J mice. Molecular and proteomic
assessment pointed to aberrant TGFb signaling with possible involvement of abnormal fibrillin
network. Disruption of the fibrillin network due to mutations in the FBN1/2 genes results in abnormal
TGFb signaling causing Marfan syndrome, which includes scoliosis and disc degeneration. These
findings are being followed up in a GRF grant awarded in 2018. Interestingly, when the transgenic
ASPN mice (normally in the C37BL background) were bred to the LG/J background, the offspring
were protected against the early-onset degenerative changes usually seen in LG/J, suggesting the
presence of protective factors against ASPN as a risk factor for IDD. A GRF project to continue this
work was obtained in 2019.
Outcome and esteem indicators
● Publications
o Early onset disc degeneration in SM/J mice is associated with ion transport systems and fibrotic
changes. Matrix Biol: S0945-053X(18)30076-3. (2018). (#98)
o Histological and reference system for the analysis of mouse intervertebral disc. J Orthop Res
236(1):233-243 (2017) (#105)
● Invited Review: Coming together is a beginning: the making of an intervertebral disc. Birth
Defects Res. C. Embryo Today 102, 83-100 (2014) (#20)
● Grants
o 2018 GRF Molecular basis of Asporin as a genetic risk factor for intervertebral disc degeneration
HK$704,862
o 2019 GRF Deciphering protective factors for intervertebral disc degeneration for mechanistic
insights and intervention potentials HK$1.02M
● Postgraduate graduations
o PhD Award: 2015 Intervertebral disc maintenance and repair potential in mice.
o MPhil Award: 2017 Cell and tissue interaction in intervertebral disc maintenance.
● Collaborations: L. Sandell, H. Lawson (Washington University, USA), J. Chevenrud (Loyola
University of Chicago, USA), C. A. Séguin ( University of Western Ontario, Canada), D. Sakai
(Tokai University, Japan)
B3. Massive progressive change in cell identities in human IVD degeneration A key prerequisite for understanding IDD is to identify the constituent cells in the NP and compare
their molecular signatures in healthy and degenerated discs. Defining a human NCC/NP signature has
been hampered by challenges in obtaining very early human embryos and have centered largely on
data obtained from cells isolated from late fetal tissue, mature NP or diseased patients and from
evolutionary correlates such as bovine. KRT8, KRT18, KRT19 and CD24 have been proposed as
human NCL-specific markers during early IVD development, but these markers are also expressed in
other tissues. We determined the molecular signatures of human NP populations at different stages of
life by sequencing RNA from single NP cells. From 610 single-cell transcriptomes of cells from human
adolescent non-degenerated NP, we identified two distinct cell populations. One comprised NCLs
because the cells expressed many NP markers; the other comprised CLCs. The NCL characteristic
genes were differentially expressed compared with degenerated NP. By comparing the NCL
characteristic genes against those expressed in 1,300 degenerated NP cells, we derived an NCL
signature comprising 40 genes, including five novel transcription factors. We found significant overlap
of the NCL gene signature with genes expressed in purified mouse notochord cells at E11.5-12.5.
We identified five subpopulations of cells in degenerated human NP with unique signatures and
regulons. Degenerative NP contains no NCLs but instead has fibroblastic cells expressing genes
characteristic of partial EMT. Three heterogeneous sub-populations of CLCs, macrophages and
myofibroblasts were found: i) a subpopulation that was closest to the CLCs present in non-degenerated
NP, designated a transition population; ii) cells expressing genes characteristic of fibroblasts,
mesenchymal cells and chondrocytes; iii) cells expressing genes associated with inflammation. We
also found a small proportion of cells expressing genes characteristic of macrophages and a significant
number of myofibroblast-like cells distinguished by a gene set that included TAGLN, ACTA2, COL1A1
and FAP. These data are consistent with NCL having a role in maintaining a healthy disc. HOPX was
identified as a candidate master regulator of NCL differentiation and identity (see above).
Inhibition of the TGFβ pathway in primary degenerated NP cells by treatment with the small
TRS6 (01/18)
molecule SB431542 decreased expression of genes characteristics of fibroblasts, consistent with the
role of the pathway in enhancing fibrosis. Studies of our GWAS population cohort of 1,400 individuals
pointed to ACTA2, a top marker of fibroblasts, as a potential risk allele for IDD, highlighting the
contribution of these cells to IDD. Overall, the presence of macrophages and myofibroblast-like cells
appears to correlate with the severity of IDD. Our study has for the first time provided a transcriptomic
analysis of NP cell populations in the human IVD at single-cell resolution with molecular insights into
IDD.
Outcome and esteem indicators
● Publication in preparation: Massive progressive change in cell identities in human
intervertebral disc degeneration. Target journal Nature Medicine (#153)
● Invited talks at international conferences: 5 invited talks - highlights are:
o “Unraveling the cell and molecular bases of intervertebral disc degeneration” Gordon Research
Conference on Collagen, , New London, USA, July 14-19, 2019 (#71)
o “Insights into the molecular pathogenesis of intervertebral disc disease at single cell resolution”
TEMTIA-IX (The 9th EMT International Association Meeting), Kumamoto, Japan, Nov 11-14,
2019 (#74)
o “Deconvoluting mechanisms of intervertebral disc degeneration by single cell analyses.”
Wellcome Trust Advanced Courses and Scientific Conferences 3rd Single Cell Biology
conference. Hinxton, UK March 11–13, 2020. (#75)
● PhD Award: 2019 Molecular insights into human intervertebral disc degeneration by single-cell
RNA sequencing
B4. A proteomic architectural landscape of the healthy and aging human intervertebral disc The progressive changes in IVD degeneration that accumulate within an ageing dis are reflected in the
proteome. We developed a comprehensive reference proteomic profile for three of the lumbar discs
(L3/4, L4/5, L5/S1) from a 16-year (young/healthy) cadaver. We mapped the proteome along the lateral
(7 segments) and anterior/posterior (5 segments) axes in each disc. Few differences were found
between the NP and inner annulus fibrosus, but these inner regions of the IVD differed considerably
from the outer annulus fibrosus regions, with potential novel markers distinguishing the inner (Col5a1,
SERPINA5, and MXRA5) and outer annulus fibrosus (THBS1/2/4, LAMB2). Consistent with the
structure and function of the IVD and mechanical loading, the most significant changes of proteins
were core matrisome, matrisome-associated proteins and ECM regulators. As expected, the upper L3/4
and L4/5 levels were more similar to each other than L5/S1.
Similar analyses of the aged/degenerative discs from a 59-year (aged) old cadaver supported a
progressive change in the matrisome, with a significant loss of “healthy” NP markers in the inner
region, and higher levels of ECM degradative enzymes, fibrotic and blood-related proteins.
Surprisingly, the proteome of the outer annulus fibrosus of aged IVDs closely resembled the profile of
a young outer annulus fibrosus, suggesting the important changes with age occur in the inner region of
the IVD. We validated key protein changes using a microarray transcriptome database. Our findings
support the hypothesis that changes in the NP predict the progression of disc degeneration.
The most significant advance in this comprehensive proteomic study is that, for the first time,
we can correlate MRI pixel intensity to matrisome signatures. We took high resolution 7 Tesla T-2
MRIs of the aged disc prior to tissue segmentation and protein extraction,and found a correlation
between the matrisome signature and MRI pixel intensity. This opens up the possibility of deriving
proteomic architecture from the pixel intensity of an MRI to obtain a spatial matrisome changes within
the IVD and to target the specific regions for therapy in the future.
Linking to therapy is to understand the dynamic of the IVD proteome. We generated proteomic
profiles of newly synthesized proteins in homeostatic (health) and aging/degenerative IVDs,and couple
these signatures with the degradome (degraded ECM components) during normal matrix remodeling
or in disease states. We showed that healthy disc cells can remodel and maintain a “homeostatic”
matrisome, able to buffer stresses induced from daily damages to the IVD. In aged IVD tissues, cells
synthesized less proteins, produced different types of ECM in an active degradative environment, and
showed cumulative and detrimental effects of cellular stress, leading to a net loss of ECM.
Significantly, the degradative environment has a negative effect on matrix assembly of newly
TRS6 (01/18)
synthesized ECM proteins in aged discs, a progressive changes in cell function with a fibrotic outcome.
Interestingly, many of the protein fragments identified are potential ‘alarmins’ – proteins that can
trigger inflammation, derived from ECM proteins, blood proteins, stress proteins and cytoplasmic
components, supporting our finding that macrophage activity in aged tissues could exacerbate
inflammation during ageing of the IVD.
Outcome
Publication: Fibrotic-like changes in degenerate human intervertebral discs revealed by
quantitative proteomic analysis. Osteoarthritis Cartilage 24:503-13 (2016). (#79)
Publication in preparation: Proteomic architecture of young and aged human lumbar
intervertebral discs. Target journal eLife (#145)
Collaboration: L. Haglund (McGill University, Canada)
B5. Clinical insights into intervertebral disc degeneration (IDD)
The relationship between IDD and low back pain has often been questioned by clinicians. We have
identified subphenotypes that help differentiate developmental from degenerative IDD. We have also
differentiated age-related changes from pathological IDD, as well as explored how such subphenotypes
are correlated with symptoms. Future work on correlating symptoms and imaging findings to omics
data will need to be based on the understanding of such subphenotypes.
Outcome and esteem indicators
Publications
o Classification and determinants of high intensity zones of the lumbar spine and its association with
other spinal MRI phenotypes: the Wakayama Spine Study. PLoS one DOI: 10.1371/journal.po
ne.0160111, 2016. (#60)
o Two subtypes of intervertebral disc degeneration distinguished by large-scale population-based
study. Spine J. pii: S1529- 9430(16)30095-X. doi: 10.1016/j.spinee.2 016.04.020, 2016 (#78)
o Classification of Schmorl’s nodes of the lumbar spine and association with disc degeneration: a
large-scale population-based MRI study. Osteoarthritis Cartilage. doi: http://dx.doi.or
g/10.1016/j.joca.20 16.04.020, 2016 (#84)
o Structural vertebral endplate nomenclature and etiology: a study by the ISSLS Spinal Phenotype
Focus Group. Eur Spine J. ;27(1):2-12, 2017 (#92).
o The UTE Disc Sign on MRI: A Novel Imaging Biomarker Associated With Degenerative Spine
Changes, Low Back Pain, and Disability Spine; 43(7):503-511.(#97)
o The association of lumbar intervertebral disc calcification on plain radiographs with
the UTE Disc Sign on MRI. European Spine Journal ; 27(5):1049-1057 2018. (#103)
Awards and invited talks
o 2014 Best Oral Short Talk. “Comprehensive analysis of MRI-phenotypes provides new insights
into lumbar disc degeneration for genetic studies” AOSpine World Forum for Spine Research,
Xian, China, May 15-17, 2014
o 2014 Best Poster. “The association of modic changes and MRI phenotypes of the lumbar spine: a
population-based study”. AOSpine World Forum for Spine Research, Xian, China, May 15-17,
2014.
o 2015 Best Paper. “Risk factors for non-neurological complications in complex audit spinal
deformity surgery: an international, large-scale, prospective multi-centre study.” AO Spine Global
Spine Congress, Buenos Aires, Argentina, May 20-23, 2015.
o 2016 ISSLS Clinical Research Prize
Grants
o 2014 RGC GRF Modic changes of the Lumbar Spine HKD$1M
B6. Genetics of IDD, extra associations with metabolic disorders and longitudinal followup
We have completed follow-up MRI assessment of our cohort of ~3,500 volunteer subjects, 5-10 years
after their initial recruitment. Genome-wide SNP genotyping was performed on 2,482 individuals, of
whom 715 also had exome sequencing. The phenotype of lumbar disc degeneration is complex, with
multiple MRI features that can be present in any of the 5 lumbar discs. From a multivariate analysis,
TRS6 (01/18)
we demonstrated that most MRI features were correlated with each other and tended to become more
frequent and severe with increasing age, whereas Schmorl’s nodes were uncorrelated with age or these
other features. We therefore proposed a classification of MRI features into degenerative and
developmental changes. With the addition of the follow-up MRI data, we have now shown that
different components of lumbar intervertebral discs (NP, annulus fibrosus and vertebral endplates)
undergo distinct but correlated degenerative changes that progress from one disc to the next, usually
from lower to upper levels.
Using genome-wide SNP data, we showed that lumbar disc degeneration had shared genetic effects
with height, body mass index and bone mineral density. Intriguingly, one component of degeneration,
modic changes in vertebral endplates, was associated with very low density lipoproteins in an
integrative analysis of genomic and metabolomic data, suggesting an interaction between local and
systemic influences on the progression of disc degeneration.
Building on our previous discoveries of susceptibility genes, we found an enrichment of association
signals in genes of the beta 3 integrin pathway, implicating integrin signalling and interactions between
cells and the ECM in disc degeneration. To increase sample size, we joined the Genetics of
Osteoarthritis consortium, which aims to perform GWAS meta analyses on osteoarthritis at different
anatomical sites (including the spine). Preliminary results indicate similarities and differences in
genetic factors between weight-bearing and non-weight bearing joints. We are now conducting
integrative analyses of all our available phenotypic and genetic data to study the genetic determinants
of all aspects of disc degeneration. In addition, our genetic analysis group has contributed to the
development of new analytical methods for genetic studies.
Outcome and esteem indicators:
Publications:o Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. J Clin Invest
123 (11), 4909-4917, 2014 (#84)
o Two subtypes of intervertebral disc degeneration distinguished by large-scale population-based
study. The Spine Journal 16 (9), 1079-1089, 2016 (#78)
o Predicting regulatory variants with composite statistics. Bioinformatics 32 (18), 2729-2736,
2016. (#80)
o Trans-ethnic polygenic analysis supports genetic overlaps of lumbar disc degeneration with
height, body mass index, and bone mineral density. Frontiers in Genetics 9, 267, 2018 (#104)
o Robust and rapid algorithms facilitate large-scale whole genome sequencing downstream analysis
in an integrative framework. Nucleic Acids Research 45 (9), e75-e75, 2017 (#95)
● Publications in preparation:o Correlated degenerative processes affecting components of lumbar intervertebral discs – a
longitudinal study using nuclear magnetic imaging. (#160)
o Integrin signalling implicated by genome-wide association study of lumbar disc degeneration in
Southern Chinese (#161)
o Reciprocal causation mixture model for mendelian randomization analysis. (#159)
o Genomic and metabolomic analyses identify very low density lipoproteins as a potential risk factor
for lumbar modic changes. (#158)
Grants:
o 2014 RGC GRF Statistical methods for characterizing the genetic component of polygenic diseases
HKD$690,089
o 2015 RGC GRF Method and software tool for estimating and dissecting the heritability of complex
diseases HKD$1,167,288
PhD awarded: 2016 Identification of common and rare genetic risk factors for lumbar disc
degeneration. 2019 Connecting the dots: Integrative analysis of genomic, metabolomic and
phenotypic data from a population cohort.
Collaboration: GO Consortium, E. Zeggini (Helmhotz Zentrum Munchen, Germany), J.
Karppinen, (Oulu University, Finland). S. Ikegawa (RIKEN, Japan).
C. TOWARDS THERAPY
We have made significant progress in defining mechanisms of skeletal dysplasia and laid the
TRS6 (01/18)
foundation for development of therapies as follows:
C1. ER stress in growth plate and bone disorders: mechanism and therapeutic potential We previously discovered a new mechanism of adaptation by chondrocytes to endoplasmic reticulum
(ER) stress, implicating this as underlying pathogenesis of skeletal disorders caused by the presence of
misfolded proteins. In the TRS programme, we defined the molecular mechanism, showing that the
Integrated Stress Response (ISR) activated by ER stress causes the chondrocyte differentiation defect
by directly activating abnormal expression of transcription factors ATF4, SOX9 and CHOP. The
survival of hypertrophic chondrocytes under ER stress requires a rebalancing of energy demand, in
which FGF21 has a role. We demonstrated that inhibition of the ISR using a small molecule alleviates
the differentiation defects, with exciting implications for the treatment of congenital dwarfism
associated with cellular stress.
We investigated the impact of ER stress on osteoblasts by studying a mouse model of
hyperostosis, an overgrowth of bone. We found that activation of the unfolded protein response in early
differentiating osteocytes delays maturation. Mechanistically, expression of SOST was perturbed,
resulting in active WNT signaling, enhancing endosteal and periosteal bone formation, and the
resultant outcome was generalized hyperostosis. The onset of hyperostosis could be suppressed with a
chemical chaperone, sodium 4-phenobutyrate (4-PBA), suggesting a possible therapeutic approach.
The hyperostosis outcome for this mouse model resembles craniodiaphyseal dysplasia, which is caused
by a dominant mutation (p.Val21Leu) in the signal peptide for cleavage of SOST. We showed that
expression of this mutation in osteoblasts activates the unfolded protein response, and thus the use of
chemical chaperones such as 4-PBA can be considered as a potential therapeutic.
Outcome and esteem indicators
Publications:
o Label-free quantitative proteomics reveals survival mechanisms developed by hypertrophic
chondrocytes under ER stress, J Proteome Res. 15(1): 86-99 (2016). (#68)
o Activating the unfolded protein response in osteocytes causes hyperostosis consistent with
craniodiaphyseal dysplasia. Human Molecular Genetics. 26(23):4572-4587 (2017)(#87)
o Inhibiting the integrated stress response prevents aberrant chondrocyte differentiation and
alleviates skeletal defects in chondrodysplasia. eLife, e37673 (2018). (#102)
Patent applications
o “Preventative and therapeutic approach for aberrant cell differentiation and ISR-associated
diseases”, International Patent Application No. PCT/IB2017/055783, Filed September 22, 2017.
o “Method for preventing or modulating fibrosis and fibrotic response associated with the
integrated stress response”, United States Patent and Trademark Office Application No.
16/335,395 filed 30 April 2019.
Invited talks at international conferences – 7 invited talks; selected highlights
as follows:
o “Genetic control of hypertrophic chondrocyte to osteoblast differentiation in development and
skeletal disorders” American Association of Anatomists (AAA) 2016 Annual Meeting, San Diego,
USA, April 2-5, 2016. (#48)
o “Inhibiting the integrated stress response prevents aberrant chondrocyte differentiation and
alleviates skeletal defects in chondrodysplasia”. 2018 Gordon Research Conference on Bones and
Teeth, Galveston , Texas, USA January 28, 2018 (#59)
o “The integrated stress response in skeletal development and disease” International Society of
Differentiation Meeting ComBio, Sydney, Australia, September 22-27, 2018. (#62)
o “Preventing and alleviating chondrodysplasia by inhibiting integrated stress response pathway”
The 11th Asian and Pan-pacific Connective Tissue Society Symposium & the 3th National Conference
of CSMB, Hangzhou, China, November 16-20, 2018. (#63)
Media coverage and the establishment of an NGO “Little People of Hong Kong”. Invited Reviews
o The extended chondrocyte lineage: implications for skeletal homeostasis and disorders. Current
Opinion in Cell Biology 61:132-140 (2019).|(#116)
o Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease. J Orthop Res
TRS6 (01/18)
2019 doi: 10.1002/jor.24523 (#112)
Award: Best poster to Postdoctoral fellow, HKU Faculty of Medicine
Knowledge Exchange Award “Little People have Talent”.
Grant: 2014 GRF Mechanisms of energy management in hypertrophic
chondrocyte adaptation to ER Stress. HK $958,840)
MPhil Award: 2017 “Energy Management in Hypertrophic Chondrocytes under
ER stress”.
Collaborations: Ray Boot-Handford (University of Manchester, UK), Alan Boyde
(University of London, UK)
C2. Developing scaffolds for maintaining notochordal and NP cells
We established several 3D culture systems which better maintained the phenotype marker expression
of bovine NPC (collagen microspheres) and mouse embryonic NCC (chemically modified collagen-
GAG scaffold and tube co-culture). We also found that the presence of the niche cells in the native
notochord is important to maintain NCC phenotype. Specifically, the presence of ECM components
such as GAG and laminin better maintained the phenotype of bovine NPC.
IDD is partially the consequence of failure in the disc capacity to maintain structural integrity
under load. We found compression loading, particularly static and high strain loading, upregulated
stress response genes including heat shock proteins and the ERS stress pathway in both 3D collagen
microspheres and IVD disc culture models. We will apply the mechanical loading system to study the
impact of different loading on NP cell gene regulatory networks. This concept forms part of the CRF
proposal currently under consideration.
Outcome and esteem indicators
Publications:
o Compression loading-induced stress responses in intervertebral disc cells encapsulated in 3D
collagen constructs. Scientific Reports 2016; 6:26449. doi: 10.1038/srep26449. (#58)
o Loading-induced heat shock response in the intervertebral disc. PLoS One. 2016
31;11(8):e0161615. doi: 10.1371/journal.pone.0161615 (#59)
Publications in preparation:
o Development of three-dimensional system for culturing notochordal cells. In preparation (#147)
o Collagen-based 3D culture systems for bovine nucleus pulposus cells (bNPCs). In preparation
(#146)
Conferences:
Keynote lecture, Microenvironment for stem cells, Tissue Engineering & Regenerative Medicine
International Society – Asia Pacific, Tamsui, Taipei, Taiwan, 3-6 September 2016. S16-01
Invited talk, Biomaterial-assisted cell-based therapy for disc degeneration, AOSpine Research
Network Meeting, Dubai, 12 Apr 2016. (#6)
PhD Award: 2016 “Development of 3D culture systems for nucleus pulposus cells.
Collaboration: B. Gantenbein, University of Bern, Switzerland
C3. Directed differentiation of mouse and human notochordal-like and NP-like cells IDD might be amenable to stem cell therapy, but the required cells are scarce. We have tested various
systems for phenotype maintenance of NCCs and NPCs. We established a notochordal explant/organ
culture system that recapitulates the notochord to NP transition for functional studies. We combined
knowledge of notochord development with the information on NCC/NPC global gene expression
patterns and developed a scheme for differentiation of mouse NotoGFP/+ ESCs towards the NCC lineage,
followed by scRNAseq profiling at various stages and comparative analyses. We were able to obtain
~25% Noto-GFP+ve cells after 4 days treatment. These cells were enriched for expression of NCC
markers.
We generated an ES reporter cell line for lineage analyses of NCC lineage derivatives. We
extended the differentiation protocol, taking guidance from the in vivo mouse NCCs/NPCs scRNAseq
data, and were able to obtain up to 70% tdTomato+ cells that were highly vacuolated and enriched for
expression of NPC markers after 25 days culture with TGF-β1 and dexamethasone. ScRNA-
sequencing of the 25-day culture revealed a cell population with high similarity to in vivo NCCs. One
TRS6 (01/18)
cluster showed strong NCL characteristics, expressing significantly more of the 52 human NCL
signature genes than others.
Concomitantly, we developed a compound-defined protocol to differentiate notochordal-like and
NP-like cells from three independent hPSC lines. Demonstration of the presence of human notochordal
and NP cells has been hampered because the characterisation of the molecular signatures of embryonic
notochord, fetal and post-natal NP cells is incomplete. NOTO is specifically expressed in the
embryonic notochord. We generated a human NOTO-eGFP knock-in ESC reporter line which we used
to monitor the endogenous activation of notochordal cell differentiation, achieving an average 14%
efficiency of differentiation of NOTO and eGFP co-expressing cells. Although, because of the
transient nature of NOTO expression, this reporter could not be used to monitor the emergence of more
mature NP cells, it allowed us to refine the conditions to a stage where we could continue
differentiation towards NP-like cells.
The second key advance is the addition of new in vivo-derived transcriptome data obtained from
the NP of human adolescent (13-14 year old) and adult (33 year old) non-degenerated discs. To our
knowledge, this is the first in depth description of the global transcriptome of young (adolescent)
human NP cells. These data have facilitated the identification of NP-like cells in the hPSC-derived
differentiated cells. We developed a bioinformatic/statistical method to probe the in vivo NP
transcriptome data for the detection and identification of NP-like cells in the differentiated cell
populations derived from hPSCs. These molecular signatures could be developed as general identity
tags to define NP cells, and more specific markers to define features of NP cells at different stages.
Importantly, application of this method enabled us to identify the presence of NP-like cells within the
hPSC-derived cells after 20 days of in vitro differentiation. We identified a set of 148 influential genes
that mark NP cell identity, which allowed us to estimate a 78% similarity between the in vivo NP cells
and the in vitro hPSC-derived cells, suggesting that we had succeeded in generating NP-like cells using
our protocol. We therefore provide the first demonstration of the derivation of human NP–like cells
with significant similarity to non-degenerated in vivo NP cells. This is a substantial advance over
previous published reports which relied on the identification of expression of a few NP markers of
limited specificity and did not provide information on differentiation efficiency or overall molecular
similarity to in vivo NP cells.
Finally, we demonstrated the biological activity of the hPSC-derived NP-like cells by their
ability, after transplantation, to attenuate the degenerative changes and/or improve the repair process
in a rat model of injury-induced disc degeneration. Overall, the hPSC-derived NP-like cells provide an
important resource for the understanding of disc cell biology with potential for the development of an
NP cell-based treatment for IDD.
Outcome
Publications in preparation:
o Directed differentiation of notochordal-like and nucleus pulposus-like cells using human
pluripotent stem cells”. Cell Reports, in revision.(#121)
o Developmental guided lineage directed differentiation of mouse notochordal and nucleus pulposus
cells Target journal eLife (#153)
Conference abstract: Presented at International Society for Stem Cell Research 2017 Annual
Meeting, Boston USA. (#57)
Grants:
o Application for CRF entitled “Functional and systems analyses of regulatory networks controlling
cell fate and lineage development of intervertebral disc cells” awaiting outcome.
o RGC matching Horizon 2020 project entitled : Induced pluripotent stem cell-based therapy for
spinal regeneration (iPSpine) HK$3M.
D. RESEARCH INFRASTRUCTURE
The TRS programme has spawned significant rich resources in terms of reagents, cell and animal
models and datasets that will facilitate research on human skeletal development and disorders with
long term impact on the field. Highlights are as follows.
D.1. Further development and sustainment of world class Transgenic Core Facility (TCF) Our world class TCF provided essential support for the TRS programme and some other Hong Kong
TRS6 (01/18)
researchers. The TCF generated more than 10 gene knockin/knockout mutants, imported 11 lines of
mutant mice, established 125 lines of transgenic/mutant mice and cryopreserved 77 mouse lines for
the TRS programme. The TCF has shared these resources with researchers in other programmes in
HKU, HKUST and CUHK. In 2018, with the completion of the TRS programme, its operation was
passed to the Faculty of Medicine where it is now a Faculty Core Facility with additional manpower.
In the process, the TRS programme donated 55 lines of genetically modified mice, comprising reporter
reagents, Cre lines and mutants for a wide spectrum of genes. One of the staff who was trained in the
TRS programme has been appointed in the new Faculty Core Facility.
D2. Platform for integrative analysis and visualization of multi-omics data (VASCO) To better manage, analyse and visualise the gigantic amounts of multi-omics data we generated in the
TRS, we developed an interactive web interface, called VASCO (Visualization and Analysis of Single-
Cell Omics) (http://hkudisc.synology.me/). The platform allows speedy query of target genes in
different types of dataset, including bulk and scRNAseq, GWAS, epi-genomics (ATAC-seq and ChIP-
seq) and proteomics. It offers versatile presentations of data, in the forms of bar charts, pie charts,
scatter-plots and chromosomal tracks, and tabulates numbers, statistics and percentages as necessary
to assist quantitative analyses. The site is highly helpful and has received over 150,000 queries since
it started operation in 2017.
D3. Rich resources for skeletal research Under TRS support, we established valuable databases (see our VASCO platform) that have enriched
and will continue to enrich skeletal research as follows:
● Human disc (MRI) phenotypes and classification for 3,500 individuals, 2,062 and 453 of whom
underwent 5-year and 10-year follow-up with accompanying genotype data, respectively.
● Bulk transcriptomes: i) healthy NP from 4 individuals; degenerated NP from 5 individuals, ii)
mouse notochordal lineage (E8.5~E10.5, E12.5, and P2 mice NP); iii) 30 profiles of annulus
fibrosus from 8 week old mice. Bulk microarray transcriptomes of AF and NP from 4 individuals.
● Single-cell transcriptomes (total over 57,000 cells) for the developing wild-type and mutant (beta
catenin null) mouse growth plate (14,286), human non-degenerated and degenerated NP (2,531
smartseq2+3,279 10X), mouse developing notochord/NP and potential progenitors (n=8,249),
mouse mature NP and neighbouring compartments (15,248), 8 week mouse AF (n=364), in vitro
differentiation-derived cells (human and mouse; n=14,654).
● Comprehensive proteomic data for mouse and human IVD: i) 66 proteomic profiles for young and
aged individuals based on liquid chromatography–mass spectrometry (LC-MS), ii) 91 profiles for
lumbar and tail NP/AF for 8-week mice based on LC-MS, iii) 8 profiles of newly synthesized
versus existing proteins based on SILAC;
● Epigenomic data of developing mouse notochord: i) ChIP-seq of E9.5, E12.5, P2, 8 week; ii) 19
profiles of ATAC-seq of E12.5, P2, and 8 week.
● GWAS (for 2121 individuals) and exome sequencing data (698 individuals).
6.2 What was the added value of the TRS funding, rather than standard project grant funding?
Working as a team has enabled research questions to be addressed at a level not possible from the
limited funding available for GRF, allowing individual PIs to undertake ambitious projects of the
scope, scale and longer term support in the TRS programme. This programme has allowed us to build
the world’s largest and most comprehensively phenotyped population based cohort of DDD subjects
and controls. The magnitude of this funding allows us to address the questions on the contribution of
genetic variation linked to detailed IDD phenotyping with more expensive techniques such as MRI
scans, genomics, GWAS and sequencing.
The funding allowed us to apply the most recent cutting edge technologies for determining cell
population heterogeneity and transcriptomes at single cell resolution and to obtain an architectural
view of the IVD proteome in both human and mouse. By such analyses, we were able to achieve
paradigm shifting insights into key developmental and disease processes: cell fate changes in the
transition from chondrocytes to osteoblasts during bone formation; the changes in cell populations
with mechanistic insights into the complex changes in the NP during human aging and IDD. The team
developed protocols for directed differentiation of mouse and human pluripotent stem cells to
TRS6 (01/18)
notochordal and early stage NP cells, demonstrating their capacity to survive transplantation
following induced disc injury, laying the foundation for future development of therapy.
As part of the TRS team, it is easier to gain technical help, advice and resources from both
local and international investigators and colleagues. This has improved the ability of individuals to
develop new approaches to problem solving, to tackle challenging research questions and to leverage
international funding.
The TRS Programme supported visits of international leaders as Scientific Advisory Board
members or as visiting lecturers. Coupled with additional funding from external bodies such as the
Croucher Foundation, the TRS programme was able to organise 7 Advanced Study Institutes on the
latest genomic and single cell technologies and stem cells which greatly facilitated the opportunities
for the team and other Hong Kong researchers at all levels to interact with internationally renowned
researchers. Building on the research activities and findings from the TRS programme, members
were able to participate in international consortiums for additional research funding, such as
Horizon 2020, with matching funds from the RGC.
6.3 If the project has not met its original objectives, why?
All objectives have been addressed.
6.4 (a) Peer-reviewed journal publication(s) arising directly from this project:
(Please attach a copy of the publication and/or the letter of acceptance if not yet submitted in the
previous progress report(s). All listed publications must acknowledge RGC’s funding
support by quoting the specific grant reference. Please mark the symbol “#” next to the
publications involving inter-institutional collaborations)
Please see Appendix I
(b) Recognised international conference(s) in which paper(s) related to this project was/were
delivered:
Team members were invited speakers and poster presenters at 106 international conferences. Under
this TRS, 116 of Journal papers have been published. 4 papers have been submitted/under review
and 40 papers are in preparation and very close to submission (Appendix I). 67 of Conference
abstracts have arisen from the TRS (Appendix II)
(c) RGC funding should have been acknowledged in all publication(s)/conference papers listed in
(a) and (b) above. If no acknowledgement has been made in any of the publications/ papers,
please indicate and provide explanations.
Not Applicable
6.5 To what extent this project has strengthened inter-institutional collaborations and other
partnerships?
We have established many fruitful collaborations in Asia, Europe and North America. K. Cheah, D.
Chan, K. Cheung and D. Samartzis, have been invited to lead international academic initiatives,
such as the World Forum for Spine Research, Gordon Research Conferences; write book chapters
and journal articles, as well as to join esteemed editorial boards. The TRS team has
strengthened existing collaborations, and built new collaborations with investigators in UK: King’s
College, USA: University of Texas Southwestern Medical Center, CalTech and University of Southern
California; Canada: University of British Columbia; Germany: Max Planck Institute for Biochemistry;
Utrecht University, the Netherlands; Eindhoven University of Technology, the Netherlands;
Washington University, USA; The University of New South Wales, Australia, Manchester University,
Genetics of Osteoarthritis (GO) Consortium; 3 EU HORIZON 2020 consortia.
6.6 Research students trained (registration/awards):
1 MPhil, 1 MRes and 15 PhD students graduated under the TRS programme.
6.7 Specific products (e.g. software or netware, instruments or equipment developed):
TRS6 (01/18)
Two patent applications were developed and filed under the TRS programme. These patents
have significant potential application not only to skeletal dysplasia but to many other
disorders especially those where fibrosis is implicated.
6.8 Other education activities and/or training programmes developed:
The TRS has contributed significantly to the community and within the university in
education, training and development. The TRS has mentored researchers at different levels of
their careers from postgraduate students to academic staff. Students, postdoctoral fellows and
junior faculty members were encouraged to organize retreats, symposia and workshops,
providing opportunities to gain organisation skills and research networking through direct
interaction with invited speakers. As an example of mentorship, Dr. Mateusz Kudelko
(postdoctoral fellow) was elected as the co-chair of the Gordon Research Seminar-Cartilage
Biology and Pathology (2019). Postdoctoral fellows participated in brain-storming sessions in
the preparation of research grant proposals by PIs, and were encouraged to apply for HMRF
research grants under the guidance of the PIs: two successfully obtained HMRF grants.
Postdoctoral fellows and students were encouraged to attend training workshops for various
research skills. A postdoc and PhD student were awarded CMB fellowships to enable them to
spend time in collaborators’ labs (UT Dallas, University of Manchester, Tokai University).
Career paths for PhD graduates have been as postdoctoral fellows, project and investment
manager in Research Institute of Tsinghua University, Shenzhen. One post-doctoral fellow has
become the vice-president of a venture capital firm. Dr, D. Samartzis secured an Associate
Professor position in Rush University, USA.
Leveraging on the TRS programme, D. Chan participated in an EU consortium “Research on
molecUlar and Biomechanical Interactions in CONnective tissue disorders” (RUBICON) for
the exchange and training of Research Fellows and PhD students, with nine other renowned
global institutions: The University of L'Aquila (Italy), Newcastle University (UK), The
University of Manchester (UK), Erasmus University Rotterdam (The Netherlands), University
of Copenhagen (Denmark), University of Cape Town (South Africa), Icahn School of Medicine
at Mount Sinai (USA), Anna University of Chennai (India) and Murdoch Children’s Research
Institute (Australia). D. Chan has received Fellows and Trainee visits from Erasmus University,
Newcastle University, The University of Manchester, and The University of L'Aquila; and sent
trainees to The University of Manchester and Erasmus University. K. Cheah is participating in
an application to Horizon 2020 for an International Training Network project “Cellular
Homeostasis ANd AGing in Connective TissuE Disorders (CHANGE).
6.9 Please highlight any deliverables indicated in the project implementation timetable endorsed by
the RGC which have not been covered or achieved as per sections 6.1 to 6.8 above, and explain/
elaborate.
Nil
Project Management
6.10 Please elaborate how the PC has played his/her role in coordinating and managing the project.
The Management Board (MB) oversees the overall research direction, progress, resource allocation,
human resources, finance and shared facilities, postgraduate education and knowledge exchange.
Progress is monitored at six monthly intervals (informally) and formally annually at a retreat, when
budget is dispersed. The process involves a critical formative self-review with discussion and input
from MB members. MB members comprise co-PIs, K. Cheah, PC as Chair. 19 MB meetings and
previous reports) and 6 budget meetings were held.
7. Awards and Recognition
TRS6 (01/18)
7.1 Have any research grants been awarded that are directly attributable to the results obtained from
this project?
In total 48 research grants have been awarded that are directly attributable to the results obtained
on this TRS projects.
7.2 Have any project team members participated as invited speakers in or organisers of international
conferences as a result of this project?
The project team members have participated as invited speakers in and organizers of
international, regional and local conferences as a result of this TRS project.
7.3 Have any project team members taken leadership positions in editorial boards, scientific and
professional organisations?
Project team members have taken leadership position in editorial boards, scientific and
professional organisation. Examples:
K. Cheah was appointed to the following Editorial and Advisory Boards:
● Board of Reviewing Editors eLife, 2019.
● Guest Associate Editor: PLoS Genetics, 2013, 2014, 2015, 2016, 2017
● Editorial Review Board Journal of Orthopedic Research, 2019 - 2021
● Senior Editor eLife June 2019-
● Editorial Advisor: Emerging Topics in Life Sciences, 2019 – 2023 (a new journal jointly-owned by
the Royal Society of Biology and the Biochemical Society (UK).
● UGC Research Assessment 2020 Biology Panel 2018-2020.
● Member, Grant Review Board for the Health and Medical Research Fund, Hong Kong (2013-
2021).
● Member, Gordon Research Conferences Hong Kong Advisory Board (2012-)
● Member, Gordon Research Conferences Board of Trustees Conference Evaluation Committee
(2018-2024).
Pak Sham was appointed to the following:
● Executive Board Member of the International Genetic Epidemiological Society (from 2018)
● Editor-in-Chief, Human Heredity (from 2018)
● Founding member of the Mapping Group of the International Common Diseases Alliance (from
2019).
Danny Chan was appointed to the following:
● Council member of the International Society of Matrix Biology (2010-2018)
● Member of the OARSI Asian Task Force on Osteoarthritis (2013-)
● Founding member, Vice President and Council member of the Chinese Society for Matrix Biology
(2016-)
● Elected Board of Directors: International Society for Differentiation (from 2018)
● Associate editor: Journal of Human Genetics (2009-)
● Editorial Board member of the journal “Matrix Biology” 2017-
● Member of the Editorial Board for Journal of Orthopaedic Research: Spine 2018 -.
Keith Luk
● President, Société Internationale de Chirurgie Orthopédique et de Traumatologie.2014-2016
● President, International Society for the Study of the Lumbar Spine. 2016-2017
● President, Asia Pacific Spine Society 2019-2021.
Ken Cheung
● President, Scoliosis Research Society. 2017 (the only non-North American to be elected
president in the society’s 50 year history).
● Chairman, World Forum for Spine Research. 2008 to 2016.
Dino Samartzis
● Editor-in-Chief - Scoliosis and Spinal Disorders Journal
● Deputy Editor - Global Spine Journal
TRS6 (01/18)
● 2017-2020 - Program Committee and Chair, International Society for the Study of the Lumbar
Spine (ISSLS)
● 2018-2021 - Chair, AOSpine International Research Commission
7.4 Any documentary proof of the application of technologies arising directly from this project?
N/A
7.5 Other awards and recognitions as a result of this project (please specify):
The team members had won 8 international, 3 local awards, 6 best paper awards, 5 best poster
awards and 2 best oral presentation awards, 7 travel awards, 3 training awards and 3 visiting
professorship and 1 senior research fellowship.
8. Impacts
8.1 What are the current and expected impacts of the project on the long-term development of Hong
Kong (social or economic development, e.g. patent, technology transfer, collaboration with
external organisations, etc.)?
● Children with rare bone diseases (Little People) and their parents often face difficulties in life
due to a lack of public awareness and misconceptions, and a lack of government and
community support. We sought to bridge communication and knowledge gaps between
affected patients, caregivers, medical professionals and the general public, whilst
simultaneously providing a platform for gaining and sharing knowledge about rare bone
diseases and treatments. Supported by the scientific and clinical knowledge base in the TRS,
and patient connections, we co-founded the “Little People of Hong Kong”, and brought
together patient groups and their families, medical professionals, schools and the general
public, to disseminate accurate information, promote inclusiveness, and to build on the positive
foundation that will make a difference. Activities included open symposia, school talks, radio
talks shows, television programmes, YouTube videos, research laboratory visits for patients,
and the publishing of a layman information book on rare skeletal diseases. Through these
activities, the team was presented with the Faculty Knowledge Exchange Award in 2017 that
provide an opportunity to initiate a “Little People have Talent” project, completed in 2018, and
showcased at the Duchess of Kent hospital Christmas Fund Raising activity.
● The wealth of data on human IVD phenotypes and IDD longitudinal follow up is a valuable
resource for further study and development of AI assisted predictive prognosis for IDD and
back pain. The two patent applications if granted will be an important source of licensing and
funding to clarify the link between EMT, HOPX, upregulated ISR and fibrosis, The successful
in vitro directed differentiation of hPSC to human NCLs and NP cells is a significant advance
and will be a foundation for work aimed at developing therapies.
8.2 Others (please specify):
9. Sustainability of the Project
9.1 Whether there are new ideas evolved directly from this project?
● With the implementation of single cell sequencing in the TRS we were motivated to employ
and develop enabling technologies for the establishment of a first of its kind atlas of human
skeletal cells across the life-span, with directly linked biophysical, transcriptome and
chromosome conformation profiles at single-cell resolution. Constructing the Human Cell
Atlas (HCA) is challenged by the enormous complexity and heterogeneity of cell types, by
their dynamic changes in intracellular signaling and biophysical properties. The biophysical
properties of a cell influence and are influenced by its molecular signature. But recording,
integrating and studying all the relevant data for individual cells requires high-throughput that
is not achievable or affordable with current technologies. Members of the TRS project have
teamed up with HK bioengineers (K. Tsia, K. Wong, H. So) to test an ultra-throughput label-
TRS6 (01/18)
free imaging technology that can capture more than a million single-cell quantitative phase
images in a single experimental run. It allows establishment of high-dimensional single-cell
biophysical phenotypic profiles (including cell size, morphology, dry-mass density and spatial
texture), with unprecedented label-free discrimination power for monitoring cell-cycle
progression not possible under high-throughput operation with existing imaging techniques.
Proof-of-concept work has yielded 2 publications [(#110) Multi-ATOM: Ultrahigh-throughput
single-cell quantitative phase imaging with subcellular resolution.J Biophotonics.
4:e201800479 (2019); (#109), Quantitative Cytometry for Ultra-Large-Scale Single-Cell
Biophysical Phenotyping. Cytometry Part A. doi: 10.1002/cyto.a.23765 (2019)]. The team
aims to seek funding to develop the transformative experimental and computational
technologies further, for the establishment of a Skeletal Cell Opto-Physical Enabled
Sequencing (SCOPES) Atlas that can generate deep biophysical profiles of single skeletal cells.
that are linked to their molecular signatures.
● V. Leung previously conducted a high-throughput screen of small molecules for modifying
IDD, and identified several leads which were characterized for their function in
inhibiting interleukin 1-mediated proteoglycan catabolism as well as therapeutic effects in
rodent and goat IDD models. The potential translation of these leads into new therapeutics for
alleviating IDD is supported by the AO Foundation, ITC-MRP to characterise the targets of
the leads for mechanistic insights.
● The correlation of genomic, proteomic, metabolomic, and 10 years of longitudinal clinical and
imaging follow up data motivates us to the develop predictive models for IDD using artificial
intelligence and deep learning. The application developed will generate IP that can be licensed
for usage by other institutions.
● Further to the work on defining optimal ECM composition for maintaining NP cells, a new
project was developed where we have designed and fabricated a new scaffold similar to that in
native NP. This scaffold will be used for IVD tissue engineering and cell therapy.
9.2 Whether there are new projects evolved directly from this project?
● To support the premise of the SCOPES project we obtained funding for a CRF project Multi-scale
single-cell optical imaging: architecture and biomedical applications. (K. Tsia PC, $7.3M) and
are seeking additional funding.
● The MRI dataset is being used to develop an automated diagnosis system based on computer vision
and artificial intelligence. A research officer within the Department of Orthopaedics and
Traumatology is contracted to work on this.
● Our transcriptome profiling implicated the MAPK pathway in regulating the differentiation of NP
cells. We plan to test the influence of MAPK inhibition on the iPS-to-NP cell differentiation
protocol.
9.3 Whether there are new collaborations developed directly from this project?
● Tencent Medial AI division (Tencent, Shenzhen, China) to develop an AI model for IDD.
● Cheah, Chan and Sham are active members of the Genetics of Osteoarthritis Consortium, a global
collaboration comprising 18 groups worldwide (E. Zeggini, Coordinator), with a focus on
understanding of the genetic bases of osteoarthritis and related traits (https://www.genetics-
osteoarthritis.com/home/index.html).
9.4 Please give details on how much money and from which sources has been obtained/requested
for the specific purpose of continuing the work started under this project.
While seeking new external funding, the transcriptomics (human and mouse), pluripotent stem cell
(PSC) and NP progenitor cell work have continued with the support of the Jimmy & Emily Tang
endowed professorship (~$1M) and HKU Research Committee Seed Funding grant ($0.5M) to K.
Cheah. A RGC CRF application (2019/20) entitled Functional and systems analyses of regulatory
networks controlling cell fate and lineage development of intervertebral disc cells to support further
development of research on human PSC-derived NP cells is currently pending the outcome. Work to
identify and characterise quiescent progenitors/stem cells in the mouse NP functionally, is supported
TRS6 (01/18)
by a GRF grant in 2019 Analyses of progenitors and differentiation trajectories in the nucleus pulposus
and their relevance in intervertebral disc degeneration. HK$ 1.5M); and work to determine the
functional relevance of NP cells expressing TAGLN and the SMAD4 pathway is supported by an
HMRF grant ($1.5M) Role(s) of TAGLN expressing cells in intervertebral disc development,
homeostasis and degeneration is supported by an HMRF grant in 2018.
10. Statistics on Research Outputs
(Please ensure the statistics in this section are consistent with the information presented in other
sections of this report.)
Peer-reviewed
journal
publications
Conference
papers
Scholarly, books,
monographs and
chapters
Patents
awarded
Other research
outputs (please
specify)
No. of outputs arising
directly from this
research project
163 74
2 filed Type No.
12. The Layman’s Summary
(describe in layman’s language the abstracts and research impact of the project.)
How genomic variation affects personal risk for degenerative skeletal disorders
基因組差異影響退化性骨骼疾病的個人風險的功能性研究
Low back pain can be intolerable for millions of people worldwide, leading to a huge
socioeconomic and health-care burden. In Hong Kong, 300,000 workdays are lost and 200
million dollars are paid for worker’s compensation. Intervertebral disc degeneration (IDD) is a
major cause of back pain, in which the cartilaginous discs between the vertebrae change in their
tissue structure and cease to function effectively to provide flexibility to the spine and protection
from mechanical loading. IDD is very common and people are affected by the age of 50 years or
older. Environmental and lifestyle factors can affect the course of disc degeneration but the
disorder also has a strong genetic component which can influence the onset and severity of
disease. However, only a few genetic factors have been identified to-date and the disease
mechanisms of IDD are poorly understood, hampering preventative measures and the
development of therapies. Key to future therapeutic and/or prognostic approaches to alleviate or
minimise the impact of IDD, is an understanding of the biology of the different components of
the spine: the discs, bone and cartilage, and mechanisms of growth, the changes accompanying
aging and causes of functional failure.
We are an internationally recognized and leading multidisciplinary team of clinicians and
scientists who have taken up the challenge, not only to identify the genetic risk factors for IDD,
but also to define how these lead to differences in the age of onset and the severity of the disease.
We used information collected about our Hong Kong population cohort, the world’s largest
group with this disorder, comprising 3,500 individuals. Data and materials included DNA
samples, spine MRI scans, demographic, environmental, lifestyle and clinical information. The
cohort was established in 2004 and participants have returned for follow up evaluation, allowing
us a unique opportunity to assess the contribution of genetics to the progression and severity of
this skeletal disorder. We have identified new subtypes of IDD, which should facilitate the
development of personalised treatment options. We have discovered several new genetic risk
factors for IDD and discovered genes and cellular signalling pathways that correlate with disease
severity, which will guide both prevention and treatment strategies. We found overlapping
genetic associations between IDD and obesity, bone mineral density and osteoarthritis, implying
TRS6 (01/18)
that these different disorders share common mechanisms, with implications for clinical
management.
We have provided significant new insights into the biology of the intervertebral disc and the
pathogenesis of IDD, using a combination of sophisticated mouse models and human tissues
from our clinical cohort. We described the molecular signatures of cells in the intervertebral disc
in terms of which genes are expressed and which proteins are present. We showed how these
change from embryonic stages to adolescence, adulthood and middle age. By integrating genetic,
molecular and clinical data, we showed that key steps in the development of IDD are two
processes common in development that are also activated in many other diseases: the cellular
stress response and a partial epithelial to mesenchymal transition that lead to a transformation in
the cellular identities of those cells that keep the tissue healthy. As a result the extracellular
matrix proteins made in the disc changes, altering the biomechanical properties and fibrosis
occurs. Discovering the mechanisms causing improper development of the growth plate that
mediates growth of bone, enabled us to identify a potential therapy. We tested an existing drug
that targets this stress response in a mouse model of congenital dwarfism with IDD, with
successful amelioration of disease symptoms. These exciting findings could form the basis for
the molecular therapy of dwarfism and IDD and possibly other skeletal disorders. We discovered
embryonic-like cells are present in the disc that are potential “stem cells”, which could be
responsible for maintenance of the healthy disc, and found that these decline with age and
degeneration, possibly explaining why disc repair becomes progressively less effective. We
developed a successful method for generating disc cells in culture from embryonic stem cells.
This landmark advance lays a strong basis for developing cell-based therapies for disc
regeneration. The outcomes of this project are contributing to achieving our mission to lay a
foundation for better prevention and treatment, thereby improving the healthcare and quality of
life for the millions of people suffering from spinal problems.
(6.4 (a) Peer-reviewed journal publication(s) arising directly from this project: (Please attach a copy of the publication and/or the letter of acceptance if not yet submitted in the previous progress
report(s). All listed publications must acknowledge RGC’s funding support by quoting the specific grant reference.
Please mark the symbol “#” next to the publications involving inter-institutional collaborations) ^ indicates Review
articles/ commentary; TRS members/staff/post-graduate students are underlined.
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1 2013 #Liu, Z.H., Sun, Z., Wang, H.Q., Ge, J., Jiang, T.S., Chen, Y.F., Ma, Y., Wang, C., Hu, S., Samartzis, D., and *Luo, Z.J.
FasL expression on human nucleus pulposus cells
contributes to the immune privilege of intervertebral disc by interacting with immunocytes. Int J Med Sci 10: 1053-
1060.
2014 No Yes Yes
2 2013 #Samartzis, D., and *Carragee,
E.J.
Preface disc degeneration for
The Spine Journal. Spine J 13: 215-
216.
2014 No Yes Yes
3 2013 #Samartzis, D., Cheung, K.M., and Cullings,
H.M.
Samartzis et al. respond. Spine J 13:
226-228.
2014 No Yes Yes
4 2013 #Samartzis, D., Ito, K., and *Wang, J.C.
Disk degeneration and pain.
Global Spine J 3: 125-126.
2014 No Yes Yes
5 2013 #Samartzis, D., Karppinen, J., Cheung, J.P., and *Lotz, J.
Disk Degeneration and Low Back Pain:
Are They Fat-Related Conditions?
Global Spine J 3: 133-144.
2014 No Yes Yes
6 2013 # Shen, F.H., and *Samartzis,
D.
Operative Management of a Sacral Gunshot
Injury via Minimally Invasive
Techniques and Instrumentation.
Asian Spine J 7: 44-49.
2014 No Yes Yes
Appendix I
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
7 2013 #Song, Y.Q., Karasugi, T.,
Cheung, K.M., Chiba, K., Ho, D.W., Miyake, A., Kao, P.Y., Sze, K.L., Yee, A., Takahashi, A., Kawaguchi, Y., Mikami, Y., Matsumoto, M.,
Togawa, D., Kanayama, M., Shi, D., Dai, J., Jiang, Q., Wu, C., Tian, W.,
Wang, N., Leong, J.C.,
Luk, K.D., Yip, S.P., Cherny,
S.S., Wang, J., Mundlos, S., Kelempisioti,
A., Eskola, P.J., Mannikko, M.,
Makela, P., Karppinen, J., Jarvelin, M.R., O'Reilly, P.F.,
Kubo, M., Kimura, T., Kubo, T.,
Toyama, Y., Mizuta, H.,
Cheah, K.S., Tsunoda, T., Sham, P.C.,
Ikegawa, S., and *Chan, D.
Lumbar disc degeneration is
linked to a carbohydrate
sulfotransferase 3 variant.
J Clin Invest 123: 4909-4917.
2014 No Yes Yes
8 2013 #Sun, Z., Guo, Y.S., Yan, S.J., Wan, Z.Y., Gao,
B., Wang, L., Liu, Z.H., Gao, Y., Samartzis, D., Lan, L.F., Wang, H.Q.,
and *Luo, Z.J.
CK8 phosphorylation
induced by compressive loads
underlies the downregulation of CK8 in human disc
degeneration by activating protein
kinase C. Lab Invest93: 1323-1330.
2014 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
9 2013 #Sun, Z., Liu, Z.H., Zhao,
X.H., Sun, L., Chen, Y.F.,
Zhang, W.L., Gao, Y., Zhang,
Y.Z., Wan, Z.Y., Samartzis, D., Wang, H.Q., and *Luo, Z.J
Impact of direct cell co-cultures on
human adipose-derived stromal
cells and nucleus pulposus cells.
J Orthop Res 31: 1804-1813.
2014 No Yes Yes
10 2013 #Sun, Z., Wang, H.Q., Liu, Z.H.,
Chang, L., Chen, Y.F., Zhang, Y.Z., Zhang, W.L., Gao, Y., Wan, Z.Y., Che, L.,
Liu, X., Samartzis, D., and *Luo, Z.J.
Down-regulated CK8 expression in
human intervertebral disc
degeneration. Int J Med Sci 10:
948-956.
2014 No Yes Yes
11 2013 #Sun, Z., Zhang, M., Zhao, X.H., Liu, Z.H., Gao, Y., Samartzis,
D., Wang, H.Q., and *Luo, Z.J.
Immune cascades in human
intervertebral disc: the pros and cons.
Int J Clin Exp Pathol 6: 1009-
1014.
2014 No Yes Yes
12 2013 #Takatalo, J., Karppinen, J., Taimela, S.,
Niinimaki, J., Laitinen, J.,
Sequeiros, R.B., Samartzis, D.,
Korpelainen, R., Nayha, S.,
Remes, J., and *Tervonen, O.
Association of abdominal obesity with lumbar disc degeneration--a
magnetic resonance imaging study. PLoS One 8:
e56244. doi:
https://doi.org/10.1371/journal.pone.005
6244
2014 No Yes Yes
13 2013 Yuan, M., Yeung, C.W., Li, Y.Y., Diao,
H., Cheung, K.M., Chan, D., Cheah, K., and
*Chan, P.B.
Effects of nucleus pulposus cell-
derived acellular matrix on the
differentiation of mesenchymal stem cells. Biomaterials
34: 3948-3961.
2014 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
14 2013 #Lv, F., Leung, V.Y., Huang, S., Huang, Y., Sun,
Y., and *Cheung, K.M.
In search of nucleus pulposus-specific
molecular markers. Rheumatology
(Oxford) 53: 600-610.
2014 No Yes Yes
15 2013 Law, T., Anthony, M.P.,
Chan, Q., Samartzis, D.,
Kim, M., Cheung, K.M., and *Khong,
P.L.
Ultrashort time-to-echo MRI of the
cartilaginous endplate: technique and association with intervertebral disc
degeneration. J Med Imaging Radiat
Oncol 57: 427-434.
2014 No Yes Yes
16 2013 #Huang, S., Leung, V.Y.,
Long, D., Chan, D., Lu, W.W., Cheung, K.M., and *Zhou, G.
Coupling of small leucine-rich
proteoglycans to hypoxic survival of a progenitor cell-
like subpopulation in Rhesus Macaque intervertebral disc. Biomaterials 34:
6548-6558.
2014 No Yes Yes
17 2013 Chen, Y.F., Zhang, Y.Z., Zhang, W.L.,
Luan, G.N., Liu, Z.H., Gao, Y.,
Wan, Z.Y., Sun, Z., Zhu, S.,
Samartzis, D., Wang, C.M., Wang, H.Q.,
and *Luo, Z.J.
Insights into the hallmarks of human
nucleus pulposus cells with particular
reference to cell viability,
phagocytic potential and long process formation. Int J
Med Sci 10: 1805-1816.
2014 No Yes Yes
18 2013 Chan, L.K., Leung, V.Y., Tam, V., Lu, W.W., Sze, K.Y., and
*Cheung, K.M.
Decellularized bovine
intervertebral disc as a natural scaffold for xenogenic cell
studies. Acta Biomater 9: 5262-
5272.
2014 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
19 2013 Chan, C.P., Kok, K.H.,
Tang, H.M., Wong, C.M.,
and *Jin, D.Y.
Internal ribosome entry site-mediated
translational regulation of ATF4
splice variant in mammalian
unfolded protein response. Biochim Biophys Acta 1833:
2165-2175.
2014 No Yes Yes
20 2014 Chan, W.C., Au, T.Y., Tam, V., Cheah, K.S.,
and *Chan, D.
Coming together is a beginning: the
making of an intervertebral disc. Birth Defects Res C
Embryo Today.;102(1):83-
100. doi:
10.1002/bdrc.21061.
2015 No Yes Yes
21 2014 Cheung KMC, Lam JWN,
Samartzis D, Lu W, *Luk KDK,
The use of a modified fulcrum
for fulcrum bending radiographs: a technical note.
Journal of Orthopaedic
Surgery Vol 22 No. 2, Pages 248-51.
2015 No Yes Yes
22 2014 Cheung, J., Samartzis, D,
*Cheung, K.M.C.
A novel approach to gradual correction
of severe spinal deformity in a
pediatric patient using the
magnetically-controlled growing rod. Spine J; 14:e7-
e13.
2015 No Yes Yes
23 2014 Cheung, J., Samartzis, D.,
Shigematsu, H., Cheung, K. M.
C.
Defining clinically-relevant values for
developmental spinal stenosis: a
large-scale magnetic resonance
imaging study. Spine; 39: 1067-76.
2015 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
24 2014 #Eskola, P.J., Mannikko, M., Samartzis, D., *Karppinen, J.
^Genome-wide association studies
of lumbar disc degeneration - are
we there yet? Spine J; 14:479-82.
2015 No Yes Yes
25 2014 Leung, V.Y., Aladin, D.M.,
Lv, F., Tam, V., Sun, Y., Lau, R.Y., Hung, S.C., Ngan,
A.H., Tang, B., Lim, C.T., Wu,
E.X., Luk, K.D.K., Lu,
W.W., Masuda, K., *Chan, D.,
*Cheung, K.M.C
Mesenchymal stem cells reduce
intervertebral disc fibrosis and
facilitate repair. Stem cells 32:2164-
77.
2015 No Yes Yes
26 2014 #Luk, K.D.K., Saw, L.B.,
Grozman, S., Cheung, K.M.C.,
*Samartzis, D.
The Spine Journal Best Paper Runner-Up - Assessment of skeletal maturity: a new classification
scheme using distal radius and ulna
radiographs. Spine J; 14:315-25.
2015 No Yes Yes
27 2014 Ma, C. J., Liu, X., Che, L., Liu,
Z., Samartzis, D., *Wang, H.
Q.
Stem cell therapies for intervertebral disc degeneration: immune privilege reinforcement by
Fas/FasL regulating machinery. Curr
Stem Cell Res; 19: 285-95.
2015 No Yes Yes
28 2014 #Samartzis D, Borthakur A,
Belfer I, Bow C, Lotz JC, Wang HQ, Cheung
KMC, Carragee E, *Karppinen J.
Novel diagnostic and prognostic
methods for disc degeneration and
low back pain. Spine J
;15(9):1919-32. doi: 10.1016/j.spinee.20
14.09.010.
2015 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
29 2014 Tam, W.K., Cheung, K.M.C.,
*Leung, V.Y.L.
Intervertebral Disc Engineering
through Exploiting Mesenchymal Stem Cells: Progress and
Perspective. Curr Stem Cell Res Ther;11(6):505-512.
2015 No Yes Yes
30 2014 Tsang, KY., Tsang, SW.,
Chan, D., and *Cheah, K.S.E
The chondrocytic journey in
endochondral bone growth and skeletal
dysplasia. Birth defects research Part C, Embryo
today: reviews 102, 52-73.
/ No Yes Yes
31 2014 #Von Forell, G., Nelson, T.,
Samartzis, D., *Bowden, A. E.
Changes in vertebral strain energy correlate with increased
presence of Schmorl’s nodes in multi-level lumbar disc degeneration. J Biomech Eng; 136:
061002.
2015 No Yes Yes
32 2014 #Wan, Z.-Y., Song, F., Sun,
Z., Chen, Y.-F., Zhang, W.-L., Ma, C.-J., Che,
L., Liu, X., Samartzis, D.,
Ali, M. A., Wang, H.-Q., *Luo, Z.-J.
Aberrantly expressed long
noncoding RNAs in human
intervertebral disc degeneration: a
microarray related study. Arthritis Res
Ther; 16: 465.
/ No Yes Yes
33 2014 Wang, H.Q., Yu, X.D., Liu,
Z.H, *Samartzis D.
Clarifying the nomenclature of
intervertebral disc degeneration and
displacement: from bench to bedside.
Int J Clin Exp Pathol; 7:1293-8.
2015 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
34 2014 Yim, R.L.-H., Lee, J., Bow,
C.H., Meij, B., Leung, V.Y.L.,
Cheung, K.M.C.,
Vavken, P., and *Samartzis, D.
A systematic review of the safety and
efficacy of mesenchymal stem
cells for disc degeneration: new insights and future
directions for regenerative therapeutics.
Stem Cells Dev 23:2553-2567
2015 No Yes Yes
35 2014 Li, Y., Diao, H., Chik, T., Chow,
S., An, X., Leung, V.,
Cheung, K., and *Chan, B.
Delivering mesenchymal stem
cells (MSCs) in collagen
microsphere carriers to rabbit
degenerative disc - Reduced risk of
osteophyte formation.
Tissue Eng PartA.20:1379-91
2014 No Yes Yes
36 2014 #Londono, D., Kou, I.,
Johnson, T.A., Sharma, S., Ogura, Y.,
Tsunoda, T., Takahashi, A.,
Matsumoto, M., Herring, J.A.,
Lam, T.P., Wang, X., Tam,
E.M., Song, Y.Q., Fan, Y.H.,
Chan, D., Cheah, K.S.,
Qiu, X., Jiang, H., Huang, D.,
Su, P., Sham, P., Cheung, K.M.,
Luk, K.D., Gordon, D.,
Qiu, Y., Cheng, J., Tang, N.,
Ikegawa, S., and *Wise, C.A.
A meta-analysis identifies adolescent idiopathic scoliosis
association with LBX1 locus in multiple ethnic groups. J Med
Genet.51:401-406
2014 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
37 2014 #Luk, K.D., Saw, L.B.,
Grozman, S., Cheung, K.M., and *Samartzis,
D.
Assessment of skeletal maturity in scoliosis patients to determine clinical
management: a new classification
scheme using distal radius and ulna
radiographs. Spine J14: 315-325.
2014 No Yes Yes
38 2014 Lv, F.J., Tuan, R.S., Cheung,
K.M., and *Leung, V.Y.
Concise review: the surface markers and identity of human
mesenchymal stem cells. Stem Cells 32:
1408-1419.
2014 No Yes Yes
39 2014 #Tam, V., Rogers, I., Chan, D.,
Leung, V.Y., and *Cheung,
K.M.
A comparison of intravenous and
intradiscal delivery of multipotential stem cells on the healing of injured intervertebral disk. J Orthop Res 32:
819-825.
2014 No Yes Yes
40 2014 Yang, L., Tsang, K.Y., Tang,
H.C., Chan, D. and *Cheah,
K.S.E.
Hypertrophic chondrocytes can
become osteoblasts and osteocytes in
endochondral bone formation.
Proc Natl Acad Sci U S A.;
111(33):12097-102. doi:
10.1073/pnas.1302703111.
2014 No Yes Yes
41 2015 #Cheung JP, Cahill P, Yaszay
B, Akbarnia BA, *Cheung
KM.
^Special article: Update on the magnetically
controlled growing rod: tips and
pitfalls. J Orthop Surg (Hong
Kong). : 23(3):383-90.
2015 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
42 2015 Cheung KMC ^Commentary on: “Symptomatic Triple-Region Spinal Stenosis
Treated with Simultaneous Surgery: Case
Report and Review of the Literature” Global Spine J,
v.5(6);
2015 No Yes Yes
43 2015 #Huang, Y.H., Jankowski, A., Cheah, K.S.E.,
*Jauch, R.
SOXE transcription factors from
selective dimers on non-compact DNA
motifs through multifaceted interactions
between dimerization and
high-mobility group domains. Nature Scientific Reports
5:10398.
2015 No Yes Yes
44 2015 Lee JTY, Cheung KMC, *Leung VYL
Extraction of RNA from tough tissues
with high proteoglycan
content by cryosection, second
phase separation and high salt precipitation.
Journal of Biological Methods,
doi: 10.14440/jbm.2015.
40
2015 No Yes Yes
45 2015 Lee, J. T., *Cheung, K. M., and *Leung, V.
Y.
Systematic study of cell isolation from
bovine nucleus pulposus:
Improving cell yield and experiment
reliability. J Orthop Res 33, 1743-1755
2015 No Yes Yes
46 2015 Luk, K. D. K., *Samartzis, D.
Intervertebral disc “dysgeneration”.
Spine J; 15: 1915-8.
2015 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
47 2015 #Maatta, J., Karppinen, J., Luk, K. D. K., Cheung, K. M. C., *Samartzis,
D.
Phenotype profiling of Modic changes
of the lumbar spine and its association
with other MRI phenotypes: a large-scale, population-based study. Spine
J; 15: 1933-42.
2015 No Yes Yes
48 2015 Samartzis D, Leung Y,
Shigematsu H, Natarajan D,
Stokes O, Mak KC, Yao G, Luk
KDK, and *Cheung KMC,
Selection of fusion levels using the fulcrum bending
radiograph for the management of
adolescent idiopathic scoliosis
patients with alternate level pedicle screw
strategy: clinical decision-making and outcomes,
PLoS One, v. 10 n. 8, p. e0120302,
DOI: http://dx.doi.org/10.1371/journal.pone.0
120302
/ No Yes Yes
49 2015 #Samartzis, D. , Gillis, C. C.,
Shih, P., O’Toole, J.E., Fessler, R.G.
Intramedullary spinal cord tumors:
Part I - epidemiology,
pathophysiology, and diagnosis.
Global Spine J; 5: 425-35.
/ No Yes Yes
50 2015 Sun, Y., Lv, M., Zhou, L., Tam,
V., Lv, F., Chan, D., Wang, H.,
Zheng, Z., *Cheung, K. M., and *Leung, V.
Y.
Enrichment of committed human nucleus pulposus cells expressing
chondroitin sulfate proteoglycans under
alginate encapsulation. Osteoarthritis
Cartilage 23(7):1194-203
2015 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
51 2015 #Sun, Z., Luo, B., Liu, Z.,
Samartzis, D., Liu, Z., Gao, B.,
Huang, L., *Luo, Z.
Adipose-derived stromal cells protect intervertebral disc
cells in compression:
implications for stem cell
regenerative disc therapy. Int J Biol Sci; 11: 133-43.
2015 No Yes Yes
52 2015 Tsang, K.Y., Chan, D.,
*Cheah, K.S.E.
^Fate of growth plate hypertrophic
chondrocytes: death or lineage extension?
Dev Growth Differ; 57(2):179-92. doi:
10.1111/dgd.12203..
2015 No Yes Yes
53 2015 #Vavken, P., Ganal-Antonio,
A. K. B., Quidde, J., Shen, F. H., Chapman, J., *Samartzis,D.
Fundamentals of clinical outcomes
assessment for spinal disorders: clinical outcome instruments and
applications. Global Spine J; 5: 329-38.
2015 No Yes Yes
54 2015 #Vavken, P., Ganal-Antonio, A. K. B., Shen, F. H., Chapman, J., *Samartzis,
D.
Fundamentals of clinical outcomes
assessment for spinal disorders: study designs,
methodologies, and analyses. Global Spine J; 5:156-64
2015 No Yes Yes
55 2015 #Von Forell, G., Stephens, T. K., *Samartzis, D., Bowden, A. E.
Low back pain: A biomechanical
rationale based on “patterns” of disc
degeneration. Spine;40(15):1165-72.
doi: 10.1097/BRS.00000
00000000982.
/ No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
56 2015 Wang Y, Cheung JP,
*Cheung KMC.
Use of PET/CT in the early diagnosis of implant related wound infection and avoidance of
wound debridement.
European Spine Journal, DOI:
10.1007/s00586-015-4044-5.
/ No Yes Yes
57 2015 #Wang, A.M., Cao, P., Yee, A.,
Chan, D., and *Wu, E.X.
Detection of extracellular matrix
degradation in intervertebral disc degeneration by
diffusion magnetic resonance
spectroscopy. Magn Reson Med;
73(5):1703-12. doi:10.1002/mrm.2
5289.
No
58 2016 Chooi WH, *Chan BP.
Compression loading-induced
stress responses in intervertebral disc cells encapsulated
in 3D collagen constructs.
Scientific Reports; 6:26449. doi:
10.1038/srep26449.
2017 No Yes No
59 2016 #Chooi WH, Chan A,
Gantenbein-Ritter B, *Chan
BP
Loading-Induced Heat Shock
Response in the Intervertebral Disc.
PLoS One. 11(8):e0161615.
doi: 10.1371/journal.pon
e.0161615
2017 No Yes No
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
60 2016 #Teraguchi, M., Samartzis, D.,
Hashizume, H., Yamada, H.,
Muraki, S., Oka, H., Cheung, J.P.-Y., Kagotani, R.,
Iwahashi, H., Tanaka, S.,
Kawaguchi, H., Nakamura, K.,
Akune, T., Cheung, K.M., Yoshimura, N., and *Yoshida,
M.
Classification and determinants of
high intensity zones of the lumbar spine and its association with other spinal MRI phenotypes:
the Wakayama Spine Study. PLoS
One DOI:
10.1371/journal.pone.0160111
2017 No Yes Yes
61 2016 #Rajasekaran, S., Kanna, R.M.,
Reddy, R.R., Natesan, S.,
Raveendran, M., Cheung,
K.M.C., Chan, D., Kao, P.Y.P., Yee, A., *Shetty
AP.
How reliable are the reported genetic
associations in disc degeneration? The
influence of phenotypes, age,
population size and inclusion sequence
in 809 patients. Spine. 41(21):1649-
1660, DOI: 10.1097/BRS.
0000000000001847
2017 No Yes Yes
62 2016 Cheung JP, Cheung PW,
Cheung KMC, *Luk KD.
Decompression without Fusion for
Low-Grade Degenerative
Spondylolisthesis. Asian Spine J. (1):75-84. doi:
10.4184/asj.2016.10.1.7
2016 No Yes Yes
63 2016 Cheung JP, Samartzis D, Cheung PW,
*Cheung KM, *Luk KD.
Reliability Analysis of the Distal Radius
and Ulna Classification for
Assessing Skeletal Maturity for Patients with Adolescent
Idiopathic Scoliosis. Global Spine J. ;6(2):164-8. doi: 10.1055/s-0035-
1557142
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
64 2016 #Dudli, S., Fields, A. J.,
Samartzis, D., Karppinen, J.,
Lotz, J. C. (2016)
Pathobiology of Modic changes. Eur
Spine J;25(11):3723-
3734.
2016 No Yes Yes
65 2016 #Ganal-Antonio, A.K.B.,
Samartzis, D., Bow, C.H.,
Cheung, K.M.C., Luk,
K.D.K, *Wong, Y.W.
Disappearing bone disease of the
humerus and the cervico-thoracic
spine: a case report with 40 year follow-up. Spine J 2:e67-
75
2016 No Yes Yes
66 2016 #Grad, S., Bow, C., Karppinen, J., Luk, K. D.
K., Cheung, K. M. C., Alini, M.,
Samartzis, D.
Systemic blood plasma CCL5 and CXCL6: potential
biomarkers for human lumbar disc
degeneration. Eur Cells Mat; 31:
1-10.
2016 No Yes Yes
67 2016 #Kamath VH, Cheung JP, Mak KC, Wong YW,
Cheung WY, Luk KD,
*Cheung KM.
Antimicrobial prophylaxis to
prevent surgical site infection in adolescent
idiopathic scoliosis patients undergoing
posterior spinal fusion: 2 doses
versus antibiotics till drain removal.
Eur Spine J. ;25(10):3242-
3248.
2016 No Yes Yes
68 2016 #Kudelko, M., Chan, C. W., Sharma, R.,
Yao, Q., Lau, E., Chu, I. K., Cheah, K. S.,
Tanner, J. A. & * Chan, D.
Label-Free Quantitative
Proteomics Reveals Survival
Mechanisms Developed by Hypertrophic
Chondrocytes under ER Stress. Journal
of Proteome Research, 15, 86-
99.
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
69 2016 Kudelko, M., Sharma, R.,
Cheah, K. S. & *Chan, D.
Comparison of proteomic datasets from hypertrophic chondrocytes in response to ER
stress. Data in Brief, 7,
449-51. doi:
10.1016/j.dib.2016.02.065.
2016 No Yes Yes
70 2016 #Liu, Z.-H. L., Huo, J.-L., Zhi-Gang, W., Sun,
Z., Bai, F., Samartzis, D.,
Gantenbein, B., Fan, S.-D.,
Wang, H. Q.
RASSF7 expression and its regulatory roles on apoptosis
in human intervertebral disc
degeneration. Int J Clin Exp
Pathol ; 8: 16097-103.
2016 No Yes Yes
71 2016 Mok, F., Samartzis, D., Karppinen, J., Fong, D. Y. T.,
Luk, K. D., Cheung, K. M.
Modic changes of the lumbar spine: prevalence, risk
factors and association with
disc degeneration and low back pain
in a large-scale population-based
cohort. Spine J; 16: 32-41.
2016 No Yes Yes
72 2016 #Samartzis, D., Bow, C. H., Cheung, J.,
Sham, P., Mak, K.-C., Cheung, W.-Y., Wong, Y.-W., Luk, K. D. K., Cheung, K., *Lawmin,
J.-C.
Efficacy of postoperative pain management using continuous local
anesthetic infusion at the iliac crest bone graft site in
adolescent idiopathic scoliosis patients: a parallel,
double-blinded,randomized
controlled pilot trial. Global Spine
J; 6: 220-8.
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
73 2016 #Samartzis, D., Cheung, J.,
Rajasekaran, S., Kawaguchi, Y.,
Acharya, S., Kawakami,
M., Satoh, S., Chen, W.-J., Park, C.-K., Lee, C.-S.,
Foocharoen, T., Nagashima, H., Kuh, S., Zheng, Z., Condor, R.,
Ito, M., Iwasaki, M., Jeong, J. H., Luk, K. D. K.,
Prijambodo, B., Rege, A., Jahng, T.-A., Luo, Z., Tassanawipas,
W. A., Acharya, N.,
Pokharel, R., Shen, Y., Ito, T.,
Zhang, Z., Aithala, J.,
Kumar, G. V., Jabir, R. A.,
Basu, S., Li, B., Moudgil, V.,
Sham, P., Williams, R.
Is lumbar facet joint tropism
developmental or secondary to
degeneration? An international, large-
scale multicenter study by the
AOSpine Asia Pacific Research
Collaboration Consortium.
Scoliosis and Spinal Disord; 11: 9.
2016 No Yes Yes
74 2016 #Samartzis, D., Gillis, C., Shih, P., O’Toole, J. E., Fessler, R.
G.
Intramedullary spinal cord tumors:
part II — management options and
outcomes. Global Spine J; 6:176-85.
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
75 2016 #Tomkins-Lane, C., Melloh, M.,
Lurie, J., Smuck, M.,
Freeman, B., Samartzis, D.,
Hu, R., Barz, T., Stuber, K.,
Schneider, M., Haig, A.,
Schizas, C., Cheung, J. P.-
Y., Mannion, A.,
Staub, L., Comer, C., Macedo, L., Ahn, S.-h.,
Takahashi, K., Sandella, D.,
Battie, M.
Consensus on the clinical diagnosis of
lumbar spinal stenosis: results of
an international Delphi study. Spine
(Phila Pa 1976); 1;41(15):1239-46.
doi: 10.1097/BRS.00000
00000001476.
2016 No Yes Yes
76 2016 #Wang W, Li TL, Wong HM, Chu PK, Kao RY, Wu S, Leung FK,
Wong TM, To MK, Cheung KM, *Yeung
KW.
Development of novel implants with
self-antibacterial performance
through in-situ growth of 1D ZnO nanowire. Colloids
Surf B Biointerfaces.
1;141:623-33. doi: 10.1016/j.colsurfb.2
016.02.036
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
77 2016 #Williams, R., Cheung, J., Goss, B.,
Rajasekaran, S., Kawaguchi, Y.,
Acharya, S., Kawakami, M., Satoh, S., Chen, W.-J., Park, C.-K., Lee, C.-S.,
Foocharoen, T., Nagashima, H., Kuh, S., Zheng, Z., Condor, R.,
Ito, M., Iwasaki, M., Jeong, J. H.,
Luk, K., Prijambodo, B., Rege, A., Jahng, T.-A., Luo, Z., Tassanawipas, W. A.,Acharya, N., Pokharel, R., Shen, Y., Ito, T.,
Zhang, Z., Aithala, J.,
Kumar, G. V., Jabir, R. A.,
Basu, S., Li, B., Moudgil, V.,
Sham, P., Samartzis, D.
An international multi-center study
assessing the role of ethnicity upon
variation of lumbar facet joint
orientation and the occurrence of degenerative
spondylolisthesis in Asia Pacific: a study from the
AOSAP Research Collaboration
Consortium. Global Spine J; 6: 35-45.
2016 No Yes Yes
78 2016 #Y. Li, D. Samartzis, D. Campbell, S.
Cherny, K. M.C. Cheung, K.D.K.
Luk, J.Karppinen,
Y.Q. Song, K. Cheah,, D.
Chan, *P.C. Sham
Two Subtypes of Intervertebral Disc
Degeneration Distinguished by
Large-scale Population-based Study. Spine J.
pii: S1529-9430(16)30095-X.
doi: 10.1016/j.spinee.20
16.04.020.
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
79 2016 Yee A., Lam P.Y., Tam V., Chan W.C.W.,
Chu I.K., Cheah K.S.E., *Cheung
K.M.C. and *Chan D
Fibrotic-like changes in
degenerate human intervertebral discs
revealed by quantitative
proteomic analysis. Osteoarthritis
Cartilage 24:503-13 (2016). Proteomic
changes in degenerate human intervertebral discs
revealed by quantitative
proteomic analysis. Osteoarthritis and
Cartilage. 24: 503-513
2016 No Yes Yes
80 2016 MJ Li, Z Pan, Z Liu, J Wu, P Wang, Y Zhu, F Xu, Z Xia, PC Sham.
Predicting regulatory variants with composite statistic Bioinformatics 32 (18), 2729-2736, 2016
No
81 2016 #Zhao Y, Wong HM, Lui SC,
Chong EY, Wu G, Zhao X,
Wang C, Pan H, Cheung KM,
Wu S, Chu PK, *Yeung KW.
Plasma Surface Functionalized
Polyetheretherketone for Enhanced
Osseo-Integration at Bone-Implant Interface. ACS
Applied Materials Interfaces;8(6):390
1-11. doi: 10.1021/acsami.5b1
0881.
2016 No Yes Yes
82 2016 #Maatta, J., Karppinen, J., Paananen, M., Bow, C., Luk,
K. D. K., Cheung, K. M.
C., Samartzis, D.
Refined phenotyping of Modic changes:
potential imaging biomarkers of
prolonged severe low back pain and
disability. Medicine.95: e3495.
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
83 2016 #Samartzis, D., Cheung, J.,
Rajasekaran, S.,Kawaguchi,
Y., Acharya, S., Kawakami,
M., Satoh, S., Chen, W.-J., Park, C.-K., Lee, C.-S.,
Foocharoen, T.,Nagashima,
H.,Kuh, S., Zheng, Z.,
Condor, R., Ito, M., Iwasaki, M.,
Jeong, J. H., Luk, K.,
Prijambodo, B., Rege, A., Jahng, T.-A., Luo, Z., Tassanawipas,
W. A., Acharya, N.,
Pokharel, R., Shen, Y., Ito, T.,
Zhang, Z., Aithala, J.,
Kumar, G. V., Jabir, R. A.,
Basu, S., Li, B., Moudgil, V.,
Goss, B., Sham, P., Williams, R.
Critical values of facet joint
angulation and tropism in the
development of lumbar degenerative
spondylolisthesis: an international,
large-scale multicenter study by the AOSpine
Asia Pacific Research
Collaboration Consortium. Global Spine J; 6: 414-21.
2016 No Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
84 2016 Samartzis, D., Mok, F. P. S.,
(Joint First Authors),
Karppinen, J., Fong, D. Y. T.,
Luk, K. D., K.,
Cheung, K. M. C.
Lumbar disc degeneration is
linked to a carbohydrate
sulfotransferase 3 variantof the lumbar
spine and association with
disc degeneration: a large-scale
population-based MRI study.
Osteoarthritis Cartilage.
doi: http://dx.doi.org/10.1016/j.joca.20
16.04.020
2016 No Yes Yes
85 2016 #Mhuiris, A. N., Volken, T., Elliott, J.,
Hoggarth, M., Samartzis, D., *Crawford, R.
Reliability of quantifying the
spatial distribution of fatty infiltration
in lumbar paravertebral
muscles using a new segmentation
method for T1-weighted MRI.
BMC Musculoskelet Disord; 17: 234.
doi: 10.1186/s12891-
016-1090-z
/ No Yes No
86 2017 # Zhang Z, Zhang Y, Gao F,
Han S, Cheah KS, Tse HF,
*Lian Q.
CRISPR/Cas9 Genome-Editing
System in Human Stem Cells: Current Status and Future
Prospects. Mol Ther Nucleic Acids. 9:230-241. doi:
10.1016/j.omtn.2017.09.009.
N/A Yes Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
87 2017 #Chan, W.C.W., Tsang, K.Y., Cheng, Y.W., Ng, V.C.W.,
Chik, H., Tan, Z.J., Boot-
Handford, R., Boyde, A., Cheung,
K.M.C., Cheah, K.S.E., and *Chan, D.
Activating the unfolded protein
response in osteocytes causes
hyperostosis consistent with
craniodiaphyseal dysplasia. Human
Molecular Genetics.doi:10.1093/hmg/dd
x339
2017 Yes Yes Yes
88 2017 #He, S., Xue, W., Duan, Z.,
Sun, Q., Li, X., Gan, H., Huang, J., and *Qu, J.Y.
Multimodal nonlinear optical
microscopy reveals critical role of kinesin-1 in
cartilage development.
Biomed Opt Express8: 1771-1782.
2017 Yes Yes Yes
89 2017 Leung V.Y., Zhou L., Tam W.K., Sun Y.,
Lv F., Zhou G., and *Cheung
K.M.
Bone morphogenetic prot
ein -2 and -7 mediate the
anabolic function of nucleus pulposus cells with discrete
mechanisms. Connect Tissue Res
19:1-13.qqq
2017 Yes Yes Yes
90 2017 #Pang, S.Y., Hsu, J.S., Teo, K.C., Li, Y.,
Kung, M.H.W., Cheah, K.S.E.,
Chan, D., Cheung,
K.M.C., Li, M., Sham, P.C., and
*Ho, S.L.
Burden of rare variants in ALS genes influences
survival in familial and sporadic ALS.
Neurobiol Aging 58: 238 e239-238 e215.
Used our HK population Cohort
as controls
2017 Yes Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
91 2017 #Wang, Y., Wu, M.H., Cheung, M.P.L., Sham,
M.H., Akiyama, H., Chan, D.,
Cheah, K.S.E., and *Cheung,
M.
Reprogramming of Dermal Fibroblasts
into Osteo-Chondrogenic Cells
with Elevated Osteogenic Potency
by Defined Transcription
Factors. Stem Cell Reports; 8(6): 1587–1599.
doi: 10.1016/j.stemcr.20
17.04.018
2017 Yes Yes Yes
92 2017 #Zehra, U., Bow, C., Lotz, J.C., Williams,
F.M.K., Rajasekaran, S., Karppinen, J., Luk, K.D.K.,
Battie, M., and *Samartzis, D.
Structural vertebral endplate
nomenclature and etiology: a study by
the ISSLS Spinal Phenotype Focus
Group. Eur Spine J.
;27(1):2-12. doi: 10.1007/s00586-
017-5292-3.
2017 Yes Yes Yes
93 2017 Liu J.AI., Rao, YX., Cheung, M.P.L., Hui, M.N., Wu,
M.H., Chan, L,K., Ng, I.O.L., Niu, B., Cheah, K.S.E., Sharma, R., Hodgson, L and *Cheung,
M.
Asymmetric localisation of
DLC1 defines avian trunk neural crest
polarity for directional
delamination and migration.
Nat Commun. ;8(1):1185. doi: 10.1038/s41467-
017-01107-0.
N/A Yes Yes N/A
94 2017 W.C.W. Chan, A.S. Shah, M.
A.Nieto, K.S.E. Cheah and *D.
Chan
Contribution of hypertrophic
chondrocytes to homeostasis of the annulus fibrosis in
normal and degenerative
intervertebral discs. Global Spine
Journal 06(S 01) · doi: 10.1055/s-0036-1582619
N/A Yes Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
95 2017 Li M, Li J, Li MJ, Pan Z, Hsu
JS, Liu DJ, Zhan X, Wang J,
Song Y, Sham PC.
Robust and rapid algorithms facilitate large-scale whole
genome sequencing downstream
analysis in an integrative
framework. Nucleic Acids Res. 2017
May 19;45(9):e75.
Yes Yes Yes
96 2017 Fan Y, Song YQ PyHLA: tests for the association between HLA
alleles and diseases. BMC
Bioinformatics. 2017 Feb
6;18(1):90.
Yes Yes Yes
97 2018 #Pang, H., Bow, C., Cheung,
JPY, Zehra, U., Borthakur, A., Karppinen, J.
Inoue, N., Wang, H.Q., Luk, K.D.K.,
Cheung, K.M.C.,
*Samartzis, D.
The UTE Disc Sign on MRI: A Novel
Imaging Biomarker Associated With
Degenerative SpineChanges, Low Back Pain, and Disability. Spine; 43(7):503-
511. doi: 10.1097/BRS.00000
00000002369..
N/A Yes Yes Yes
98 2018 #Zhang Y, Xiong C,
Kudelko M, Li Y, Wang C,
Wong YL, Tam V, Rai MF, Cheverud J, Lawson HA,
Sandell L, Chan WCW, Cheah
KSE, Sham PC, *Chan D
Early onset disc degeneration in SM/J mice is
associated with ion transport systems
and fibrotic changes.
Matrix Biol. pii: S0945-053X
(18)30076-3. doi: 10.1016/j.matbio.20
18.03.024.
N/A Yes Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
99 2018 Yuan MT, Pai PJ, Liu XF, Lam
H, *Chan BP.
Proteomic Analysis of Nucleus
Pulposus Cell-derived
Extracellular Matrix Niche and Its Effect
on Phenotypic Alteration of
Dermal Fibroblasts.Scientific Reports
8(1), 1512 https://doi.org/10.10
38/s41598-018-19931-9
N/A Yes Yes Yes
100 2018 Wang, Y.X., Leung, K.K.H.,
Sham, M.H., Chan, D.,
Cheah, K.S.E and *Cheung M.
Reprogramming of mouse calvarial osteoblasts into
induced pluripotent stem cells. Stem
Cells InternationalVolume, Article ID 5280793, 11 pages
https://doi.org/10.1155/2018/5280793
N/A Yes Yes Yes
101 2018 ZJ Tan, B Niu, KY Tsang, IG Melhado, S.
Ohba, X. He, A. P. McMahon,
Y.H. Huang, R. Jauch, M.Q
Zhang, D. Chan, *KSE Cheah.
Synergistic co-regulation and
competition by a SOX9-GLI-FOXA
phasic transcriptional
network coordinate chondrocyte
differentiation transitions. PLoS Genet
; 14(4): e1007346.doi:
10.1371/journal.pgen.1007346
N/A Yes Yes Yes
102 2018 C. Wang, Z. Tan, K.Y.
Tsang, K. K. H. Leung, N. Dung, B. Niu, D. Ron,
D. Chan, *K.S.E. Cheah.
Inhibiting the integrated stress
response pathway prevents aberrant
chondrocyte differentiation
thereby alleviating chondrodysplasia.eLife.; 7: e37673.
doi: 10.7554/eLife.3767
3
N/A Yes Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
103 2018 Zehra,U., Bow, C., Cheung,
JPY, Pang H., Lu, W.
Samartzis, D.*
The association of lumbar
intervertebral disc calcification on
plain radiographs with the UTE Disc
Sign on MRI. European Spine
Journal ; 27(5):1049-1057.
doi: 10.1007/s00586-
017-5312-3. Epub 2017 Oct 9.
N/A Yes Yes N/A
104 2018 X. Zhou, Y. Li, J. Karppinen, Y-
Q Song, C-L. Cheung, D.
Samartzis, D. Chan, S. Ikegawa,
K.M.C. Cheung, arcOGEN
Consortium, K.S.E. Cheah,
and *P. C. Sham
Trans-ethnic polygenic analysis supports genetic
overlap of lumbar disc degeneration with height, body mass index, and
bone mineral density.
Front Genet; 9: 267.doi:
10.3389/fgene.2018.00267
N/A Yes Yes N/A
105 2018 Tam, V., Chan W, Leung V,
Cheah K, Cheung K, Sakai D,,
McCann MR, Bedore J,
Séguin CA, *Chan, D.
Histological and reference system for
the analysis of mouse
intervertebral disc.J Orthop Res. ;
36(1):233-243. doi: 10.1002/jor.23637.
N/A Yes Yes No
106 2018 Cheung, J., Kao, P., Pak, S., Cheah, K., Chan, D.,
Cheung, K., and *Samartzis, D.
Etiology of developmental
spinal stenosis: a genome-wide
association study. J Orthop Res.
;3 6(4):1262-1268. doi:
10.1002/jor.23746..
N/A Yes Yes No
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
107 2018 Sun Y, Leung VYL, *Cheung
KMC
Clinical trials of intervertebral disc
regeneration: current status and
future developments. Int
Orthop. doi: 10.1007/s00264-
018-4245-8
N/A Yes Yes N/A
108 2019 Lee K.S., Yip M.S., Lam T.K.,
Song Y.Q., Cheah K.S.E.,
Cheung K.M.C. and Chan Danny.
Molecular basis of Asporin as a genetic
risk factor for intervertebral disc
degeneration. Matrix Biology
Europe Meeting, Manchester,
England, July 21-24, 2018.
International Journal of
Experimental Pathology, 99(6):
A34.
N/A Yes Yes N/A
10098 2019 LyF, Cheung KMC, Zheng ZM, Wang H,
Sakai D, Leung VYL
IVD progenitor cells: a new horizon for understanding disc homeostasis and repair. Nature
Reviews Rheumatology 15, p102-112 January
2019. DOI: 10.1038/s41584-
018-0154-x
N/A Yes Yes N/A
11009 2019 Lee KCM, Wang M, Cheah KSE, Chan GCF, So HKH, Wong KKY, Tsia KK.
Quantitative Phase Imaging Flow Cytometry for
Ultra-Large-Scale Single-Cell Biophysical
Phenotyping. Cytometry A. 2019 May;95(5):510-520.
doi: 10.1002/cyto.a.2376
5. Epub 2019 Apr 22.
Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1110 2019 Lee KCM, Lau AKS, Tang
AHL, Wang M, Mok ATY,
Chung BMF, Yan W, Shum
HC, Cheah KSE, Chan
GCF, So HKH, Wong KKY,
Tsia KK.
Multi-ATOM: Ultrahigh-throughput single-cell quantitative phase imaging with subcellular resolution. J Biophotonics. 2019 Jul;12(7):e201800479. doi:10.1002/jbio.201800479. Epub 2019 Apr 1
Yes Yes
1121 2019 #F. Chen, W.C.W.
Chan,Y. Lam, X. Wang, P.
Chen, B. Niu, Ng V.C.W.,J.C. Yeo, S. Stricker, K.S.E. Cheah, M. Koch, S.
Mundlos, H.H. Ng and D. Chan
Lgr5 and Col22a1 Mark Progenitor
Cells in the Lineage toward Juvenile
Articular Chondrocytes, Stem Cell Reports, 13: 1-
17, doi.org/10.1016/j.stemcr.2019.08.006
Yes Yes
1132 2019 #D.A. Kaji, Z.J. Tan, G.L. Johnson, W. Huang, K. Vasquez, J.A. Lehoczky, *B. Levi, *K.S.E. Cheah, *A.H. Huang.
Cellular plasticity in musculoskeletal
development, regeneration, and disease. J Orthop
Res. doi: 10.1002/jor.24523.
[Epub ahead of print] Review.
PMID: 31721278
Yes Yes
1143 2019 #S. A. Ali, B. Niu, K.S.E. Cheah, *B. Alman.
Unique and overlapping GLI1
and GLI2 transcriptional
targets in neoplastic chondrocytes.
PLoS One. 29;14(1):e0211333.
doi: 10.1371/journal.pon
e.0211333.
N/A Yes Yes Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1154 2019 #Takeda K, Kou I, Otomo N, Grauers A, Fan YH, Ogura Y, Takahashi Y, Momozawa Y, Einarsdottir E, Kere J; Japan Scoliosis Clinical Research Group (JSCRG), Matsumoto M, Qiu Y, Song YQ, Gerdhem P, Watanabe K, Ikegawa S.
A multiethnic meta-analysis defined the
association of rs12946942 with severe adolescent
idiopathic scoliosis. J Hum Genet. 2019 May;64(5):493-498.
Yes yes yes
1165 2019 Yip, R.K.H, Chan, D.,
*Cheah, K.S.E.
Mechanisitic insights into
skeletal development gained
from genetic disorders. Current
topics in Developmental
Biology
N/A Yes Yes
1176 2019 Tsang KY, *Cheah, K.S.E.
The extended chondrocyte
lineage: implications for
skeletal homeostasis and disorders.
Current Opinion in Cell Biology
Yes Yes
118 2020 Y. Zhang, Z. Zhang, P.
Chen, C.Y. Ma, C. Li,
T.Y.K. Au, V. Tam, Y. Peng, R. Wu, K.M.C. Cheung, P. C.
Sham, H.F. Tse, D. Chan, V.Y. Leung,
*K.S. E.Cheah, *Q.
Lian.
Directed differentiation of notochordal-like
and nucleus pulposus-like cells
using human pluripotent stem
cells. Cell Reportsin revision.
N/A N/A Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1197 2019 Au, T.Y., Lam, T.K., Peng, Y,
Wynn, S. Cheung, K.M.,
Cheah K.S., *Leung V.Y..
Transformation of resident notochord-descendent nucleus
pulposus cells in mouse injury-
induced fibrotic intervertebral discs.
Under review by Aging Cell.
N/A N/A Yes N/A
12018 Yes #Chen, L., Peng, S., Zhou, X.,
Long, D., Pan, H., Leung, V. Y., Lu, W. W.,
Wu, N., Song, Y.,
Huang, S., Li, W., Samartzis,
D.
Ipriflavone is safe and effective in postmenopausal
women with osteopenia or
osteoporosis: a systematic review and meta-analysis.
Lancet.
N/A N/A Yes N/A
12119 Yes #Samartzis, D., Karppinen, J.,
Lotz, J. C.
Degenerative disc disease. Lancet;
N/A N/A Yes N/A
1220 Yes #Stokes O., Fung G., Mak
K.C., Luk K.D.K.,
*Samartzis D.
A problematic "dens". Global Spine J; (Under
Review)
N/A N/A Yes N/A
121 Yes Y. Zhang, Z. Zhang, P. Chen, C.Y. Ma, C. Li, T.Y.K. Au, V. Tam, Y. Peng, R. Wu, K.M.C. Cheung, P. C. Sham, H.F. Tse, D. Chan, V.Y. Leung, *K.S. E.Cheah, *Q. Lian.
Directed differentiation of notochordal-like
and nucleus pulposus-like cells
using human pluripotent stem
cells. Cell Reportsin revision.
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1232 Yes K. S. Lee, M. S. Yip, T.K. Lam,
Y.Q. Song, K.M.C. Cheung K.S.E. Cheah,
&*D. Chan
Asporin induces TGFb signalling and intervertebral disc degeneration
via disruption of the fribrillin matrix. (Target Journal:
Nature Communications)
N/A N/A Yes N/A
1243 Yes Y Zhang, Z Zhang, PK
Chen, S. Richardson, J.A. Hoyland, K.S.E. Cheah and *Q.
Lian
Common and distinct molecular signatures between hESC/iPSCs and
adult tissue-derived NPC-like cells reveal putative
pathways involved in healthy and degenerative
conditions (Target journal: Cell Stem
Cell or Nature Communications)
N/A N/A Yes N/A
1254 Yes CW Cheng, KY Tsang, S Guo, KS Lee, WCW Chan, D Chan, *KSE Cheah.
Single cell analyses of adult nucleus pulposus of the
intervertebral disc reveal heterogeneity
and slow-cycling cells with
stem/progenitor properties. (Target journal: Cell Stem
Cell/Nature Communications.)
N/A N/A Yes
1264 Yes C. Zhang, F Lim, S.M.
Richardson, W.K. Tam, T.Y. Au, D. Chan,
R.S. Tuan, J.A. Hoyland, K.S.E.
Cheah, K.M. Cheung, and *V.Y. Leung.
N-cadherin modulates
mechanosensensingand notochordal cell fate. (Target journal:
PNAS/ PLoS Biology)
N/A N/A Yes
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1275 Yes CW Cheng, KY Tsang, S Guo, KS Lee, WCW Chan, D Chan,
*KSE Cheah.K.Y.
Tsang, H. S.W. Tsang. R.K.H.
Yip, J. Gu X. Li, Y. Yang, D. Chan, MQ
Zhang, *K.S.E. Cheah
Single cell analyses of adult nucleus pulposus of the
intervertebral disc reveal heterogeneity
and slow-cycling cells with
stem/progenitor properties. (Target journal: Cell Stem
Cell/Nature Communications.)Transition states and
Wnt control of lineage trajectories in chondrocyte to osteoblast trans-differentiation. (Target journal:
Nature Cell Biology /Developmental Cell, Cell Stem
Cell)
N/A N/A Yes N/A
1286 Yes S. Guo, T.Y. Au, S.L. Wynn,
K.K.H. Leung, A. Aszodi, R.
Fassler, D. Chan, *K.S.E.
Cheah
β1 integrin regulates
convergent extension in mouse notogenesis. (Target
journal: Development).
N/A N/A Yes N/A
1297 Yes T.Y. Au, R.K.H. Yip, S. Wynn,
I.Y.Y.Szeto, T.Y. Tan, Y.H. Geng, K.M.C. Cheung, K.D.K. Luk, D. Chan, R. Lovell-Badge, *K.S.E
Cheah.
Sox9Y440X mutation causes campomelia by dysregulation of osteogenesis and
hedgehog signaling. (Target journal:
PNAS)
N/A N/A Yes N/A
13028 Yes T.Y. Au, B.Niu, R.M.H. Wu,
Y.Qin, K. T.T. Ng, K.K. Tong,
J. Wang, D. Chan, P.C.
Sham, M.Q. Zhang, R.Ng, *K.S.E Cheah.
Systems biology assisted lineage
directed differentiation of notochordal cells.
(Target journal: Cell Stem Cell/Cell Reports/PLoS
Biology/ELife).
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
13129 Yes I.Y.Y. Szeto, R.M.H.Wu, B
Niu, A.S.L. Wong., *K.S.E.
Cheah.
MicroRNA-mRNA regulator networks
promote notochordal cell fate in
directing differentiation of embryonic stem
cells. (Target journal: Cell Stem
Cell/Cell Reports/PLoS
Biology/ELife).
N/A N/A Yes N/A
1320 Yes S. Guo, P.K. Chen, T. Au, B. Niu, Z. Tan K.Y. Tsang, R. Wu,
S.M. Richardson, J.A.
Hoyland, D. Samartzis, J.
Cheung, K.D.K. Luk, K.M.C. Cheung, D. Chan, M.Q.
Zhang, R.Ng, P.C. Sham,
*K.S.E Cheah.
Molecular signatures of single
cell in human intervertebral discs
reveal heterogeneity, senescence and
decline of notochordal-like
cells in intervertebral disc
degeneration (Target journal:
Journal of Clinical Investigation)
N/A N/A Yes N/A
1331 Yes P. Kao, M. S. Yip Y. Li, K. L. Sze, A. Fosang, D. McCulloch,
K.M.C. Cheung, K.D.K. Luk, J. Karppinen, K. Cheah, P. C.
Sham, Y. Song and *D. Chan
Association and functional analysis
of ADAMTS5 in lumbar disc
degeneration. (Target journal: The
Spine Journal).
N/A N/A Yes N/A
1342 Yes Y. Li, D. Samartzis,
K.M.C. Cheung, K.D.K. Luk, J. Karppinen, Y.
Song, D. Chan, K.S.E. Cheah,
and *P.C.Sham.
Novel genetic risk factors identified from a genome-wide association study for lumbar
disc degeneration in Southern Chinese.
(Target journal: European Journal
of Human Genetics)
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1353 Yes Y. Li, D. Samartzis,
K.M.C. Cheung, K.D.K. Luk, J. Karppinen, Y.
Song, K. Cheah, D. Chan and *P.
C. Sham
Plasma metabolites as mediators of
genetic factors for weight, height and intervertebral disc
degeneration. (Target journal:
American Journal of Human Genetics)
N/A N/A Yes N/A
1364 Yes P.K. Chen, S.Guo, Y. Li, T. Au, Z. Tan, B. Niu, R.Wu, D. Samartzis, J. Cheung, K.
M.C. Cheung, K.D.K. Luk, J. Karppinen, Y.
Song, D. Chan, R. Ng, P. C.
Sham and *K. Cheah
Integrative systems approach implicate
cellular stress pathways leading to
calcification in intervertebral disc
degeneration. (Target journal:
Nature Medicine)
N/A N/A Yes N/A
1375 Yes Y. Qin, P.K. Chen, Y. Li, J.
Wang, P. C. Sham, K.
Cheah, *R. Ng
Active enhancer-transcription factor interactions in the
development of the nucleus pulposis in
mouse. (Target journal: Genome
Biology)
N/A N/A Yes N/A
1386 Yes Y. Qin, J. Wang, K. Cheah and *P. C Sham
Modelling transcriptional regulation via sparse group
LASSO. (Target journal:
Bioinformatics).
N/A N/A Yes N/A
1397 Yes Z J. Tan, B. Niu, C.Wang K. Y. Tsang, M.Q.
Zhang, D. Chan and
*K.S.E.Cheah
The RNAome of the ER stressed growth plate identify novel UPR target genes.
(Target journal: Journal of Cell Biology, PLoS
Genetics).
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
14038 Yes C.Wang, Z J. Tan, W.C.W. Chan, A.S. Shah, K. Y.
Tsang, D. Chan and *K.S.E.
Cheah.
Selective Inhibition of the Integrated Stress Response
Ameliorates premature
intervertebral disc degeneration
(Target Journal: J. Clinical
Investigation or Science
Translational Medicine).
N/A N/A Yes N/A
14139 Yes #Samartzis D, Karppinen J,
Cheah K, Chan D, Cheung, JPY,
Luk KDK, Cheung
KMC, Sham P.*
10 year longitudinal follow-up study of
lumbar disc degeneration.
(Target Journal: Arthritis and Rheumatism)
N/A N/A Yes N/A
1420 Yes #Samartzis D, Karppinen J,
Cheah K, Chan D, Cheung, JPY,
Luk KDK, Cheung
KMC, Sham P*
10 year longitudinal study of lumbar
MRI phenotypes. (Target Journal:
Arthritis and Rheumatism)
N/A N/A Yes N/A
1431 Yes #Samartzis D, Karppinen J,
Bow C, Cheah K, Chan D,
Cheung, JPY, Luk KDK,
Sham P, Cheung KMC*.
Natural history and risk factors of low
back pain and sciatica: a 10 year longitudinal study(Target Journal: J Bone and Joint
Surgery)
N/A N/A Yes N/A
1442 Yes Cheung, P., Tam, V., Leung, V. Y., Samartzis, D., Cheung, K. M. C., Luk, K. D. K., *Cheung, J. P.-Y.
The relationship of ligamentum flavum
changes and developmental lumbar spinal
stenosis. Scoliosis and Spinal Disorder.
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1453 Yes C.C.Y Chan., M.Y Choi., Luk K.D.K, D Chan,
J.A Tanner, *K.S.E Cheah.
Redundant function and dose dependent
requirement for Sedlin and
Sedlin-like protein in development. Target journal J.
Cell Biology
N/A N/A Yes N/A
1464 Yes M. Kudelko, R. Sharma, Y.
Zhang, R. Ramalingam,
W. C.W. Chan, T. Y.K. Au, B. Niu, V. Tam, Y. W. Lam,
K.S.E. Cheah and *D. Chan
Label-Free Proteomic
Comparison of Murine
Intervertebral Disc Across Gender,
Level and Structures. (Target
Journal: Matrix Biology.)
N/A N/A Yes N/A
1475 Yes #V Tam, P Chen, M
Kudelko, W Chan, A Guo, L
Haglund, K Cheah KSE Cheah, *D
Chan.
Proteomic architecture of
young and aged human lumbar
intervertebral discs. (Target journal
eLife) A proteomic
landscape of the human lumbar
intervertebral disc
(Target journal: eLife)
N/A N/A Yes N/A
1486 Yes Li HY, Chooi WH, Huang N, Li YY, Chan D, Cheah K, Chan
BP*
Collagen-based 3D culture systems for
bovine nucleus pulposus cells
(bNPCs). (Target journal: Scientific
Reports)
N/A N/A Yes N/A
1497 Yes Yuan MT, Yeung CC, Au TYK, Chan D, Cheah KSE, *Chan BP.
Development of Three-Dimensional
System for Culturing
Notochordal Cells. (Target journal: Biomaterials)
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
15048 Yes M. Kudelko, R. Sharma, Y.
Zhang, W.CW Chan, T. Y. Au, B.Niu, H.Kong, R.Ramalingam, V. Tam, Y. W.
Lam, K.S.E. Cheah and *D.
Chan
Comparative Proteomics of Heathy Murine
Intervertebral Discs: Gender, Level and Structure. Target Journal: Matrix
Biology
N/A N/A Yes N/A
15149 Yes #V. Tam, P.K. Chen, A.Yee,
M. Kudelko,W. C.W Chan,
K.SE Cheah, L. Haglund and Danny Chan
A Proteomic Architectural Landscape of
Healthy and Aging Human
Intervertebral Discs. Target Journal:
eLife
N/A N/A Yes N/A
1520 Yes K.S. Lee, M.S. Yip, T.K. Lam, M. Kudelko, Y.
Zhang, Y.L.Wong,
K.SE Cheah, Y. Q. Song, and
*D. Chan
Over expression of Asporin in the
mouse intervertebral disc
induces chondrogenic and fibrotic events via activation of TGFb signaling. Target Journal: Human
Mol. Genet.
N/A N/A Yes N/A
1531 Yes #W.CW Chan, A. M. Shah,
D.Vimalagopalan, Y. Zhang, A.
Nieto, K.SE Cheah and
*Danny Chan
Transition of endplate
hypertrophic chondrocytes to annulus fibrosus
cells via epithelial to mesenchymal
transition for intervertebral disc
homeostasis. Target Journal:
undecided
N/A N/A Yes N/A
1542 Yes T.Y. Au, R.M.H. Wu, P.K. Chen,
B.Niu, D. Chan, P.C. Sham,
M.Q. Zhang, *K.S.E Cheah.
Developmental guided lineage
directed differentiation of
mouse notochordal and nucleus
pulposus cells. (Target journal: Cell
Stem Cell/Cell Reports/PLoS
Biology/eLife).
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1553 Yes #S.,Guo, P.K.Chen, TYK
Au., V.Tam, B.Niu, K.Y. Tsang, S.M.
Richardson, J.A Hoyland., D.
Sakai, D. Samartzis, J.
Cheung, K.D.K. Luk, K.M.C
Cheung, M.Q. Zhang, Chan
D., Sham P.C., *Cheah K.S.E
MassiveDramatic progressive change in cell identities in
human intervertebral disc
degeneration (Target journal:
Nature Medicine)
N/A N/A Yes N/A
1564 Yes #S. Guo, P.K. Chen, T. Au, R.
Wu, V. Tam, S.M.
Richardson, J.A. Hoyland, J. D.
Sakai, J. Cheung, K.M.C.
Cheung, D. Chan, M.Q.
Zhang, *K.S.E Cheah
HOPX maintains notochordal-like progenitor cell
identity of human nucleus pulposus
cells. Target journal Nature Medicine SM/J maintains notochordal-like progenitor cell
identity of human nucleus pulposus
cells
N/A N/A Yes N/A
1575 Yes #K.Y. Tsang, X. Li, T.L. Chu,
M. P. Kong, H. S.W. Tsang, J.
Gu, Y. Yang, D. Chan, M.Q.
Zhang, *K.S.E. Cheah
Transition states and beta catenin
control of lineage trajectories in chondrocyte to
osteoblast trans-differentiation. (Target journal
eLife/Developmental Cell).
N/A N/A Yes N/A
1586 Yes T. L. Chu, K.Y.Tsang, M.
P. Kong, D. Chan, Z. Zhou, *K.S.E. Cheah
MMP14 cleaves PTH1R, regulating the contribution of the chondrocyte-osteoblast lineage
continuum to bone. Target journal
Nature Cell Biology/J Clinical
Investigation
N/A N/A Yes N/A
The Latest Status of Publications Author(s) (denote the
corresponding author with an
asterisk*)
Title and journal/book (with the volume, pages
and other necessary publishing details
specified)
Submitted to the RGC
(indicate the year ending of
the relevant progress report)
Attached to this report (Yes or
No)
Acknow- ledged the support of
RGC (Yes or
No)
Accessible from the
institutional repository (Yes or No)
Year of publication
Year of acceptance (for paper accepted
but not yet published)
Under review
Under preparat
ion (optiona
l)
1597 Yes #Z. Tan, M. Kong, S. Wen, K.Y. Tsang, B. Niu, D. Chan,
C.C. Hui, *K.S.E. Cheah.
IRX3 and IRX5 inhibit adipogenic differentiation of
hypertrophic chondrocytes and
promote osteogenesis. Target
journal J Clinical Investigation.
N/A N/A Yes N/A
160 Yes Li Y, Chen G, Qin Y, Chan
PK, Samartzis, Cheung KMC, Chan D, Cheah KSE, Sham PC.
Genomic and metabolomic
analyses identify very low density lipoproteins as
potential risk factor for lumbar modic
changes.
N/A N/A Yes N/A
161 Yes Liu Z, Qin Y, Wu T,Mak
TSH, Zhang Y, Li MX, Sham
PC.
Reciprocal causation mixture
model for mendelian
randomization analysis.
N/A N/A Yes N/A
162 Yes Li Y, Chen G, Qin Y, Chan
PK, Samartzis, Cheung KMC, Chan D, Cheah KSE, Sham PC.
Correlated degenerative
processes affecting components of
lumbar intervertebral discs
– a longitudinalstudy using nuclear magnetic imaging.
N/A N/A Yes N/A
163 Yes Li Y, Kao P, Zhou X, Cheung
KMC, Luk KDK,
Karppinen J, Song YQ,
Cheak KSE, Chan D, Sham
PC.
Integrin signalling implicated by genome-wide
association study of lumbar disc degeneration in
Southern Chinese.
N/A N/A Yes N/A
6.4 (b) Recognised international conference(s) in which paper(s) related to
this project was/were delivered: (Please attach a copy of each conference abstract) *Please note that Gordon Research
Conferences have policy that all presentations are priviledged and no abstracts are
published.
Month/
Year/
Place
Title Conference name Submitted
to the
RGC
(indicate
the year
ending
of the
relevant
progress
report)
Attached
to this
report
(Yes or
No)
Acknowledged
the support of
the RGC
(Yes or No)
Accessible
from the
institutional
repository
(Yes or No)
1 March 2019, Houston, USA
Label-Free Proteomic Comparison of Murine Intervertebral Disc Across Gender, Level and Structure
Gordon Conference , Cartilage Biology and Pathology
No No Yes Yes
2 Sept 2019, Stockholm, Sweden
Role of Pax1 in the homeostasis of the spine and pathogenesis of Adolescent Idiopathic Scoliosis
International Consortium for Spinal Genetics, Development and Disease
No Yes Yes No
3 Sept 2019, Sydney, Australia
The proteomic landscape of the young and aged lumbar intervertebral disc
2nd Sydney Spinal Symposium
No no Yes No
4 Nov 2019, Pennsylvania, USA
The proteomic landscape of the young and aged lumbar intervertebral disc
ORS PSRS 5th International Spine Research Symposium
No no Yes No
5 2019 Insights into the cellular basis of intervertebral disc disease gained from the transcriptomes of single cells.
Gordon Research Conference on Cartilage Biology and Pathology.
No no Yes No
6 Feb 15, 2019. Korea
Insights into the cellular basis of intervertebral disc disease gained from the transcriptomes of single cells
2019 Annual meeting of Korean Society for Cartilage and Osteoarthritis.
No Yes Yes No
7 2019 Ultrafast label-free imaging cytometry enables massive and in-depth single-cell
CYTO conference 2019. No Yes Yes No
Appendix II
biophysical phenotyping,
8 2019 MAP kinase interference promotes the nucleus pulposus progenitor-like differentiation of mesenchymal stem cells.
International Consortium for Spinal Genetics, Development and Disease, Stockholm, Sweden
No Yes Yes No
9 2019 Kyoto, Japan
Promoting Nucleus Pulposus Progenitors-like Differentiation From Mesenchymal Stem Cells Via MAP Kinase Interference Coupled Chondrogenic Induction.
The Annual Meeting of the International Society for the Study of the Lumbar Spine,
No Yes Yes No
10 June 2019 Santiago, Chile
Pathway for becoming a spine deformity surgeon Assessment of sagittal balance to prevent complications Neurological deterioration, prevention and management My guidelines for reduction Complications in adult deformity – lessons from Scolirisk study. 20 years’ experience in degenerative disc disease research: What have I learnt?
AOSpine Regional Course
No Yes Yes No
11 Sept 2018 Cambridge,
Mini-Spine: an Ex-vivo Mouse Model
Engineering Multicellular Self-
No Yes Yes No
United Kingdom
System for Functional Studies on the Notochord and Nucleus Pulposus
Organisation III
12 March 2018 in Hinxton
An integrative bioinformatics approach for establishing transcriptomic identities of single-cell populations
Wellcome meeting No Yes Yes No
13 April 2018 Hong Kong
20 years’ experience in degenerative disc didease: What have we learnt
The 15th HK Int’l Orthopaedic Forum
No Yes Yes No
14 June 2018 Taipei, Taiwan
Future direction of spinal care: Genetics, Disc regeneration and Artificial intelligence
Asia Pacific Spine Society annual meeting
No Yes Yes No
15 May 2018 St. Petersburg, Russia
Modern surgery for spinal deformities in skeletal dysplasia and syndromal scoliosis Degenerative disc disease – challenging traditional reliefs Scoliosis Research Society (SRS) past, present and future
Scoliosis Research Society Worldwide Course wit the IX Congress of the Russian Association of Spinal Surgeons
No Yes Yes No
16 April 2018 Istanbul Turkey
Form lab to bench-side: Thinking outside the box
Acibadem Mehmet Ali Aydinlar University
No Yes Yes No
17 April 2018 Antalya, Turkey
Decision making in degenerative deformity High grade slip: to reduce or not?
20th Asia Pacific Orthopaedic Association Congress
No Yes Yes No
Thinking outside the box in spine deformity care
18 April 24, 2018, Instituto de Neurociencias CSIC-UMH, Spain
Chondrocyte plasticity in development & disease
Mini-Symposium “Cell plasticity in development and disease”
No Yes Yes No
19 January 28, 2018, Galveston, TX, USA.
Molecular control of the trans-differentiation of hypertrophic chondrocyte to osteoblast in skeletal development and growth
2018 Gordon Conference on Bones and Teeth
No Yes Yes No
20 Sep 22-27, 2018. Sydney, Australia,
The integrated stress response in skeletal development and disease
International Society of Differentiation Meeting ComBio 2018
No Yes Yes No
21 2018 Hong Kong
Single cell analyses of human intervertebral discs implicate HOPX as a regulator of homeostasis
SBMS Research Day, School of Biomedical Sciences, The University of Hong Kong. 2018.
No Yes Yes No
22 2018 New Orleans, USA
Myofibroblast differentiation in disc degeneration: a possible contribution of local and non-local cells.
64th Annual Meeting of Orthopaedic Research Society
No Yes Yes No
23 2018 Davos, Switzerland
Deriving Nucleus Pulposus-like Progenitors from MAP kinase Interference Coupled Chondrogenic Induction in Mesenchymal stem cells.
eCM XVIII Cartilage & Disc: Repair and Regeneration
No Yes Yes No
24 2017 Lucca
Development of Intervertebral disc degeneration in N-cadherin mutant mouse.
Gordon Research Conference: Cartilage Biology & Pathology
No Yes Yes No
25 2017 Philadelphia, USA
Myofibroblast differentiation in disc degeneration: a possible contribution of local and non-local cells.
ORS 4th International Spine Research Symposium
No Yes Yes No
26 2017 Athens
Development of lumbar disc degeneration in cadherin 2 mouse mutant.
The Annual Meeting of the International Society for the Study of the Lumbar Spine, Athens.
No Yes Yes No
27 2017 Philadelphia, USA.
Myofibroblast differentiation in disc degeneration: a possible contribution of local and non-local cells
ORS 4th International Spine Research Symposium
No Yes Yes No
28 2017 Hong Kong
Genome-wide identification of active enhancers in the developing mouse nucleus pulposus,
2017 Hong Kong Inter-University Postgraduate Symposium in Biochemical Sciences.
No Yes Yes No
29 2017 Hong Kong
FGF21 Up-Regulates Glycolytic Proteins for Hypertrophic Chondrocyte Survival under ER Stress
2017 Hong Kong Inter-University Postgraduate Symposium in Biochemical Sciences.
No Yes Yes No
30 May 26-30, 2017, Stockholm.
Single cell transcriptomes reveal a mesenchymal state during chondrocyte to osteoblast transition.
Keystone Symposium Single Cell Omics
No Yes Yes No
31 2017 Lucca. Development of Intervertebral disc degeneration in N-cadherin mutant mouse
Gordon Research Conference: Cartilage Biology & Pathology
No Yes Yes No
32 2017 Athens Development of lumbar disc degeneration in cadherin 2 mouse mutant
The Annual Meeting of the International Society for the Study of the Lumbar Spine
No Yes Yes No
33 2017 Developing Strategies to Produce Notochord Like Cells from Human ESC/iPSC
International Society for Stem Cell Research 2017 Annual Meeting.
No Yes Yes No
34 2017 MMP14 and Regulation of the Hypertrophic Chondrocyte to Osteoblast Lineage
2017 Hong Kong Inter-University Postgraduate Symposium in Biochemical Sciences.
No Yes Yes No
35 April 2-7, 2017, Lucca (Barga), Italy
Chondrocyte Plasticity and Fate Determination in Development and Disease
Gordon Research Conference on Cartilage Biology & pathology. Gordon Research Conference on Cartilage Biology & Pathology.
No Yes Yes No
36 June 2017, Singapore
Mechanisms of chondrocyte adaptation and survival under ER stress
18th International Congress of Developmental Biology
No Yes Yes No
37 Nov 2017 Hong Kong
Aetiology of intervertebral disc degeneration: implications on motion preservation and regeneration
The HK Orthopaedic Association Annual
No Yes Yes No
38 Nov 2017 San Diego USA
Thinking outside the box on a global scale
11th Int’l Congress on Early Onset Scoliosis
No Yes Yes No
39 Dec 2017 Yamagatoa, Japan
Management of degenerative spinal deformities
第 20 回山形脊椎
懇話
No Yes Yes No
40 May 29-June 2, 2017 Athens, Greece.
Structural vertebral endplate nomenclature and etiology: a study by the ISSLS Spine Phenotype Focus Group.
44th Annual Meeting of the International Society for the Study of the Lumbar Spine.
No Yes Yes No
41 May 29-June 2, 2017 Athens, Greece.
Lumbar high‐
intensity zones on MRI: imaging biomarkers for severe, prolonged low back pain and sciatica in a
population‐based
cohort.
44th Annual Meeting of the International Society for the Study of the Lumbar Spine.
No Yes Yes No
42 May 29-June 2, 2017 Athens, Greece.
Radiographic indices for lumbar developmental spinal stenosis.
44th Annual Meeting of the International Society for the Study of the Lumbar Spine.
No Yes Yes No
43 May 29-June 2, 2017 Athens, Greece.
Coexisting cervical and lumbar disc degeneration and associated MRI phenotypes: a
large‐scale
population‐based
study.
44th Annual Meeting of the International Society for the Study of the Lumbar Spine.
No Yes Yes No
44 July 2017 Hong Kong
Genome-wide Identification of Active Enhancers in the Developing Mouse Nucleus Pulposus
Gordon Research Conference on Genome Architecture in Cell Fate & Disease
No Yes Yes No
45 June 2017, The Chinese University of Hong Kong, Hong Kong
Regulation of cell fate decision by microRNA in the mesendoderm lineage
Gordon Research Conference: Germinal Stem Cells
No Yes Yes No
46 July 2017, The Hong Kong University of Science and Technology, Hong Kong
Regulation of cell fate decision by microRNA in the notochordal lineage
Gordon Research Conference: Genome Architecture in Cell Fate and Disease
No Yes Yes No
47 April, 2017 Lucca, Italy
Mechanistic Insights into ER Stress Induced Skeletal Defects Identify Therapeutic Opportunities (Oral and poster presentation)
Gordon Research Seminar: Comprehending Cartilage Formation, Function and Failure for Improving Joint Health
No Yes Yes No
48 April, 2017 Lucca, Italy
Mechanistic Insights into ER Stress Induced Skeletal Defects Identify Therapeutic Opportunities
Gordon Research Conference: Understanding Biology to Achieve Better Cartilage Health
No Yes Yes No
49 May, 2017 Athens, Greece
Lumbar paravertebral muscle fatty infiltration: Relationship of distribution patterns to demographics, disability and pain
44th Annual Meeting of the International Society for the Study of the Lumbar Spine
No Yes Yes No
50 May, 2017 Athens, Greece
Lumbar high-intensity zones on MRI: imaging biomarkers for severe, prolonged low back pain and sciatica in a population- based cohort
44th Annual Meeting of the International Society for the Study of the Lumbar Spine
No Yes Yes No
51 May, 2017 Athens, Greece
Coexisting cervical and lumbar disc degeneration and associated MRI phenotypes:
44th Annual Meeting of the International Society for the Study of the Lumbar Spine
No Yes Yes No
a large-scale population- based study
52 May, 2017 Athens, Greece
Multi-dimensional assessment of vertebral endplate breaks on MRI: implications in spine degeneration and pain/disability
44th Annual Meeting of the International Society for the Study of the Lumbar Spine
No Yes Yes No
53 May, 2017 Athens, Greece
Vertebral Endplate Abnormalities Highly Associated with Thoracic Disc Herniations in Symptomatic Patients
44th Annual Meeting of the International Society for the Study of the Lumbar Spine
No Yes Yes No
54 April, 2017 Lucca, Italy
Differential roles of Hif-1α and Hif-2α in biosynthesis of chondrocyte specific extracellular matrix
Gordon Research Conference: Understanding Biology to Achieve Better Cartilage Health
No Yes Yes No
55 April, 2017 Australia
Development of lumbar disc degeneration in cadherin 2 mouse mutant
ISSLS Annual Meeting
No Yes Yes No
56 May 2017, Stockholm
Single cell transcriptomes reveal a mesenchymal state during chondrocyte to osteoblast transition.
Keystone Symposium Single Cell Omics
No Yes Yes No
57 June 2017, Boston, USA
Developing Strategies to Produce Notochord Like Cells from Human ESC/iPSC
ISSCR 2017 Annual Meeting
No Yes Yes No
58 July, 2017 University of
MMP14 regulates Lineage Progression
Gordon Research Conference:Matrix Metalloproteinases
No Yes Yes No
New England USA
of Hypertrophic Chondrocytes to osteoblasts
59 April, 2017 Lucca, Italy
Synergistic co-regulation and competition underlies a SOX9-GLI- FOXA phasic transcriptional network that coordinates growth plate chondrocyte differentiation (Best poster presentation prize)
Gordon Research Seminar: Comprehending Cartilage Formation, Function and Failure for Improving Joint Health
No Yes Yes No
60 April, 2017 Lucca, Italy
Synergistic co-regulation and competition underlies a SOX9-GLI- FOXA phasic transcriptional network that coordinates growth plate chondrocyte differentiation (Best poster presentation prize)
Gordon Research Conference: Understanding Biology to Achieve Better Cartilage Health
No Yes Yes No
61 April, 2017 Lucca, Italy
Proteomic Landscape of murine Intervertebral disc reveals mechanisms involved in homeostasis and disc structure maintenance (Oral and poster presentation)
Gordon Research Seminar: Comprehending Cartilage Formation, Function and Failure for Improving Joint Health
No Yes Yes No
62 April, 2017 Lucca, Italy
Proteomic Landscape of murine Intervertebral disc
Gordon Research Conference: Understanding
No Yes Yes No
reveals mechanisms involved in homeostasis and disc structure maintenance
Biology to Achieve Better Cartilage Health
63 December, 2016, The University of Hong Kong
MMP14 regulates Lineage Progression of Hypertrophic Chondrocytes (Best oral presentation prize) (Champion)
21th Rsearch Postgraduate Symposium,
No Yes Yes No
64 September, 2016, Taipei, Taiwan
Reconstitution of nucleus pulposus cell matrix niche in 3D collagen microspheres
Tissue Engineering and Regenerative Medicine International Society- Asia Pacific Meeting
No Yes Yes No
65 13-16 Apr 2016, Dubai
Collagen Microspheres—A Three-Dimensional Culture System for Notochordal Cells.
World Forum for Spine Research, WST004.
No Yes Yes No
66 13-16 Apr 2016, Dubai
Compression Loading Induced Cellular Stress Response of Intervertebral Disc Cells in Organ Culture.
World Forum for Spine Research, WST009.
No Yes Yes No
67 13-16 Apr 2016, Dubai
Chooi WH, Chan BP. Compression Induced Stress Response of Nucleus Pulposus Cells in 3D Collagen Gel.
World Forum for Spine Research, WST005.
No Yes Yes No
68 October 2016 Suzhou, China
Genome-wide Identification of Active Enhancers in the Developing Mouse Nucleus Pulposus
Systems Biology of Gene Regulation and Genome Editing
No Yes Yes No
69 December 2016
Chondrocyte plasticity,
The 9th Guangzhou
No Yes Yes No
Guangzhou, China
adaptation and survival under ER stress
International Conference on Stem Cell and Regenerative Medicine
70 2016 Orlando, USA
Cadherin2/N-cadherin Deficiency In Nucleus Pulposus Causes Loss Of Cell Vacuolation And Disc Integrity.
62nd Annual Meeting of Orthopaedic Research Society
No Yes Yes No
71 December 20- 21, 2016, Guangzhou, PR China.
Chondrocyte plasticity, adaptation and survival under ER stress.
9th International Conference on Stem Cell and Regenerative Medicine
No Yes Yes No
72 2015 Philadelphia, USA
Nucleus Pulposus Cell Vacuolation: A New Perspective From N-Cadherin/Cadherin 2 Function.
ORS 3rd International Spine Research Symposium,
No Yes Yes No
73 2014 Xian, China
Cadherin 2 is required for intervertebral disc homeostasis and maintenance of vacuolated phenotype in nucleus pulposus cells.
World Forum for Spine Research,
No Yes Yes No
74 December 2016 Guangzhou, China
Chondrocyte plasticity, adaptation and survival under ER stress
The 9th Guangzhou International Conference on Stem Cell and Regenerative Medicine
No Yes Yes No