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Pulmonary Biology
Jamie Havrilak, PhDPostdoctoral Research Associate
Layden LabOctober 30th, 2017
Nkx2.1- Lung epitheliumEndomucin- Vasculature
http://depts.washington.edu/envh/lung.html
Alveoli/Capillaries: Site of Gas Exchange in the Lung
Alveoli/Capillaries: Site of Gas Exchange in the Lung
Capillary
CO2
O2
Vein
Artery
Air
Alveoli/Capillaries: Site of Gas Exchange in the Lung
Capillary
CO2
O2
Vein
Artery
Air
Nkx2.1- epitheliumEndomucin- blood vesselsSMA-smooth muscle
Alveolar Surface Area= 350-400 sq ft (100-150 m2)Respired Air – 11,000 liters/day
http://www.eurostemcell.org/factsheet/lung-stem-cells-health-repair-and-disease
Generation and organization of cell types
Distal Alveolus
Lung Diseases
• Respiratory Distress (RDS)
• Bronchopulmonary Dysplasia (BPD)
• Congenital Diaphragmatic Hernia (CDH)
• Asthma
• Pulmonary hypertension
• Lung Cancer
• Emphysema
• COPD
• Cystic fibrosis
Cystic Fibrosis
Common Lung Diseases
• Respiratory Distress (RDS)• Chronic lung diseases of early infancy (BPD)• Congenital Diaphragmatic Hernia (CDH)• Asthma• Pulmonary hypertension• Lung Cancer• Emphysema• COPD• Cystic fibrosis• Why study lung development?• If we understand how the lung develops, we can
figure out how to repair it.
Stages of Human and Mouse Lung Development
Lungs continue to develop after birth
Havrilak and Shannon, 2015
Conception
Bud initiation
Branching morphogenesisbegins
Embryonic
Alveolar
Pseudoglandular
Canalicular
Saccular
Formation of alveoli
Surfactant synthesis begins
Human (weeks):
Mouse (days): E12
7w
E16
17w
E17
26w
PN4
38w
PN14
18m
E9
3w
Patterning is complete
Alveoli numberincreasesBirth
Conception
Bud initiation
Branching morphogenesisbegins
Embryonic
Alveolar
Pseudoglandular
Canalicular
Saccular
Formation of alveoli
Surfactant synthesis begins
Human (weeks):
Mouse (days): E12
7w
E16
17w
E17
26w
PN4
38w
PN14
18m
E9
3w
Patterning is complete
Alveoli numberincreasesBirth
Premature Birth
Respiratory DistressDisrupts Lung Development
Havrilak and Shannon, 2015
Each of the germ layers gives rise to many different cell types
Developmental Biology, 9e, Figure 1.7
Image from Zorn and Wells, 2009
The tracheal groove, arising from the foregut endoderm, branches to give rise to the conducting airways
Early Stages of Lung Development
I. Embryonic
Image modified from the Pulmonary Biology Division websitehttp://www.cincinnatichildrens.org/research/div/pulmonary-biology/faculty-research/whitsett-lab/projects.htm
Nkx2.1- Lung epitheliumEndomucin- Vasculature
I. Embryonic
Havrilak and Shannon, Lung Development 2015
II. Pseudoglandular II. Pseudoglandular
I. Embryonic
II. Pseudoglandular
I. Embryonic II. Pseudoglandular III. Canalicular V. AlveolarIV. Saccular
Image modified from the Pulmonary Biology Division websitehttp://www.cincinnatichildrens.org/research/div/pulmonary-biology/faculty-research/whitsett-lab/projects.htm
Later Stages of Lung Development in the Mouse
III. Canalicular IV. Saccular
V. Alveolar
V. Alveolar
V. Alveolar
Tissue interactions govern early lung morphogenesis
Importance of Lung Mesenchyme
• Lung mesenchyme is essential for lung development
• Branching and differentiation of the epithelium depends on a close association with the lung mesenchyme. Mesenchyme
Epithelium
Wessells, 1970
Lung mesenchyme is necessary for lung epithelial branching
Lung Mesenchyme (M) Attracts Lung Epithelium (E)
EM
Mesenchymal inducers are diffusible
Lung epithelial development driven by mesenchymal signals
Rankin and Zorn, 2015, J. Cell Biochem.
How do we induce lung bud formation?
FGF signaling is an essential component of the regulatory networks between epithelium and mesenchyme in the developing lung
Deletion of FGF10 results in lung agenesis, as does deletion of its receptor FGFR2b.
Image modified from Cardoso and Kotton, 2008
Fgf10- is expressed in distal lung mesenchymeSignals to Fgf receptors in epithelium
Image modified from Sekine, et al.,1999
Image modified from Min, et al.,1998 Genes and Dev
Interactions Between Multiple Signaling Pathways
When?Where?How much?
Rankin and Zorn, 2015, J. Cell Biochem.
Gene regulatory network governing respiratory specification
Lung Morphogenesis and Differentiation
40 Cell Types
Need to Orchestrate Proper:
Place
Time
Cell Types
Cell Numbers
Size
Function
Repair
Regulation of Processes:
Commitment
Specification
Restriction
Differentiation
Proliferation
Maturation
Morphogenesis
Patterning
Translational applications
• Currently no effective treatments – Respiratory distress syndrome
– Chronic obstructive pulmonary disease
– Idiopathic pulmonary fibrosis
• Pathways that are activated during development may be activated during adult lung repair
• Model human disease
• New or improved clinical therapies
Pluripotent stem cell (PSC)-derived organoids.
Meritxell Huch, and Bon-Kyoung Koo Development 2015;142:3113-3125
© 2015. Published by The Company of Biologists Ltd
Induced pluripotent stem cell (iPSC)
https://research.cchmc.org/stemcell/iPSC
Meritxell Huch, and Bon-Kyoung Koo Development 2015;142:3113-3125
Go through many different stages before it can become a lung cell
Rankin and Zorn, 2015, J. Cell Biochem.
How do we make a lung in a dish?
Briana R Dye et al. eLife Sciences 2015;4:e05098
Lung spheroids
Briana R Dye et al. eLife Sciences 2015;4:e05098
Briana R Dye et al. eLife Sciences 2015;4:e05098
Chen, et al., 2017, Nature Cell Biology
3D Lung Organoids
Potential application of lung organoids in modeling human diseases
Chen, et al., 2017, Nature Cell Biology
