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UNIVERSITI PUTRA MALAYSIA
THERAPEUTIC POTENTIALS OF BONE MARROW DERIVED
MESENCHYMAL STEM CELLS IN AVERTING ORGAN DAMAGE DUE TO RIFAMPICIN INDUCED TOXICITY IN ANIMAL MODEL
DANJUMA LAWAL
FPSK(P) 2018 38
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THERAPEUTIC POTENTIALS OF BONE MARROW DERIVED
MESENCHYMAL STEM CELLS IN AVERTING ORGAN DAMAGE DUE
TO RIFAMPICIN INDUCED TOXICITY IN ANIMAL MODEL
By
DANJUMA LAWAL
Thesis Submitted to the School of Graduate Studies, Universiti Putra Malaysia,
in Fulfillment of the Requirements for the Degree Doctor of Philosophy
Febuary 2018
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COPYRIGHT
All material contained within the thesis, including without limitation text, logos,
icons, photographs, and all other artwork, is copyright material of Universiti Putra
Malaysia unless otherwise stated. Use may be made of any material contained within
the thesis for non-commercial purposes from the copyright holder. Commercial use
of material may only be made with the express, prior, written permission of
Universiti Putra Malaysia.
Copyright © Universiti Putra Malaysia
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DEDICATIONS
To the memory of my beloved father may his soul rest in peace, and my beloved
mother both of them have been everything to me.
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Abstract of thesis presented to the Senate of Universiti Putra Malaysia in fulfilment
of the requirement for the degree of Doctor of Philosophy
THERAPEUTIC POTENTIALS OF BONE MARROW DERIVED
MESENCHYMAL STEM CELLS IN AVERTING ORGAN DAMAGE DUE
TO RIFAMPICIN INDUCED TOXICITY IN ANIMAL MODEL
By
DANJUMA LAWAL
Febuary 2018
Chairman : Suresh Kumar Subbiah, PhD
Faculty : Medicine and Health Sciences
Being the front line medicine against tuberculosis, rifampicin has been used for quite
a long period of time. Although it is still effective in killing the bacteria, the drug has
been shown to be associated with many adverse effects, like liver and kidney
toxicity. Investigations of toxicological effects due to rifampicin treatment have been
published since 1974. Just few years after the drug became available in the market
and more and more articles are still published showing its adverse effects on liver
and kidney. Yet the drug is still prescribed and considered the best option. Prolong
rifampicin therapy due to tuberculosis and the toxicity of the drug; coupled with the
proportionate risk of kidney/liver malfunction has stressed the need for a new
interventional approach. Intravenous administration of bone marrow mesenchymal
stem cells along with rifampicin can yield a promising result. This is because the
hepatocytes and renal cells growth factors that are known to have multiple function
like stimulating antiapoptotic and antioxidant actions that can neutralized the
toxicological impacts of the drug can be released by the MSCs. Also the ability of
the transplanted MSCs to differentiate into liver and kidney cells can help in the
organ regeneration as well. This research was design to assess the therapeutic
potential of MSCs in averting organ damage due to rifampicin-induced liver and
kidney toxicity on wistar rats and their progeny. Both male and female wistar rats
were given the therapeutic doses of rifampicin via oral gavage (9mg/kg/day for
3month), rifampicin plus MSCs infusion intravenously 2.5x105cells (twice/month for
3-months), and a control group received normal saline only via oral gavage.
Alteration in biochemical indicators like ALT, AST, total bilirubin, albumin, total
cholesterol, triglycerides, LDL-cholesterol level, HDL-cholesterol level, urea,
creatinine, total protein were found. Pathological changes in both liver and kidney of
the rifampicin treated rats like necrosis of hepatocytes, cytoplasmic vacuolation,
distended sinusoids, loss of polyhedral structure in the liver, hypertrophied of kupper
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cells in sinusoids, degeneration of liver cells, hypertrophy of hepatocytes, with
pycnotic nuclei and deformed nuclei, disorganization of hepatocytes with lysis of
cytoplasm. Pathological changes in kidney like increase in size of glomeruli and
degeneration of renal tubules were also noticed. In order to determine if these effects
can be transferred to their progeny, both the males and females were breed (while the
treatments continue during the breeding) and the biochemical markers and the
histopathological damages in the progeny were assessed. Transplanted MSCs was
able to avert these effects by the release of growth factors and also by the
differentiation potentials of the cells to both the liver and kidney cells. Transplanted
MSCs showed a promising hepatic and renal protection against rifampicin induced
toxicity in wistar rats and their progeny; as seen in both the biochemistry and
histological data, therefore it can be used in conjunction with the antituberculosis
drug rifampicin. Furthermore, gene expression studies revealed some genes that
were either up regulated or down regulated due to the adverse effects of the drug, but
were gradually returning back to their normal fold change value as a result of the
stem cell treatment. It can be concluded that administration of bone marrow-derived
mesenchymal stem cells have shown some modulatory, regenerative and therapeutic
activity against liver and kidney injury due to prolonged rifampicin treatment in
Wistar rats and their progenies as seen both in the biochemical indicators,
histological assessment, cell quantification and also the gene expression studies.
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Abstrak tesis yang dikemukakan kepada Senat Universiti Putra Malaysia sebagai
memenuhi keperluan untuk ijazah Doktor Falsafah
POTENSI TERAPEUTIK SEL STEM MESENKIMAL DARI SUM-SUM
TULANG DALAM MENGHINDARI KEROSAKAN ORGAN AKIBAT DARI
KETOKSIKAN DIARUH OLEH RIFAMPISIN DALAM MODEL HAIWAN
Oleh
DANJUMA LAWAL
Februari 2018
Pengerusi : Suresh Kumar Subbiah, PhD
Fakulti : Perubatan dan Sains Kesihatan
Sebagai ubat rawatan utama bagi jangkitan tuberkulosis, rifampisin telah lama
digunakan. Walaupun masih efektif dalam membunuh bakteria ini, rifampisin
dikaitkan dengan pelbagai kesan sampingan seperti kesan toksik pada hati dan buah
pinggang. Penyelidikan mengenai kesan tosikologi penggunaan rifampisin telah
diterbitkan semenjak tahun 1974. Beberapa tahun selepas ubatan ini berada di
pasaran dan semakin banyak artikel yang diterbitkan telah membincangkan
mengenai kesan sampingannya. Walau bagaimanapun, ubat ini masih digunakan dan
masih lagi di ertimbangkan sebagai pilihan yang terbaik untuk rawatan tuberkulosis.
Pengambilan terapi rifampisin dalam jangka masa yang lama dan tahap toksik ubatan
ini, ditambah dengan kesan kepada kegagalan fungsi buah pinggang/hati telah
menyebabkan satu kaedah lain diperlukan untuk pendekatan intervensi baru.
Penyaluran sel stem mesenkimal (MSCs) dari sum-sum tulang secara interavenus
bersama dengan rifampisin mampu memberikan keputusan yang
memberangsangkan. Oleh kerana sel hepatosit dan faktor penggalak sel renal telah
diketahui mempunyai pelbagai fungsi dalam menggalakan kesan anti-apoptosis dan
antioksidan dalam meneuteralkan impak toksikologikal ubatan ini dan kebolehan
MSCs untuk berubah kepada sel hati dan sel buah pinggang, kedua-dua fenomena ini
dijangka dapat membantu dalam pembaikian organ tersebut. Penyelidikan ini
dibentuk bertujuan untuk mengetahui potensi terapeutik penggunaan MSCs dalam
pengurangan kesan kerosakan organ akibat dari penggunaan rifampisin yang
menyumbang kepada toksiksiti kepada hati dan buah pinggang bagi tikus wistar dan
keturunannya, Tikus wistar jantan dan betina telah diberikan dos terapeutik
rifampisin 9mg/kg/hari untuk 4 bulan, rifampisin dan MSCs 2 kali/sebulan untuk
tempoh 3 bulan infusi secara intravena serta kumpulan kawalan yang hanya
menerima larutan salin sahaja menerusi oral ‘gavage’. Perubahan dalam indikator
biokimia seperti ALT, AST, jumlah bilirubin, albumin, jumlah kolesterol, trigliserid,
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paras kolesterol LDL, paras kolesterol HDL, urea, kreatinin, jumlah protein juga
telah direkodkan serta perubahan patologikal dalam hati dan buah pinggang juga
telah dikesan dalam tikus yang diberikan rifampisin seperti nekrosis pada hepatosit,
vakuol sitoplasmik, pengembangan sinusoid, perubahan struktur polihedral pada sel
hati, pembesaran pada sel kupper dalam sinusoid, penguraian sel hati, hipertropi
pada hepatosit serta nuklei yang ‘pycnotik’ dan nuklei yang tidak sempurna,
hepatosit yang tidak teratur dengan sitoplasma yang telah pecah. Buah pinggang juga
mengalami perubahan patologikal seperti penambahan saiz glomeruli serta
penguraian tubul renal juga telah diambil perhatian. Untuk meneliti adakah kesan ini
diwarisi kepada keturunan tikus ini, kedua-dua tikus jantan dan betina telah
dikacukkan dan penanda biokimia dan kerosakan histopatologikal kepada keturunan
telah disiasat. MSCs yang di transplan telah berjaya membendung kesan buruk
ubatan ini dengan penghasilan faktor pembesaran dan juga potensi pembiakan sel
bagi kedua-dua sel hati dan buah pinggang. MSCs yang di transplan menunjukkan
perlindungan yang memberangsangkan kepada heptik dan renal terhadap rifampisin
yang di rangsangkan dalam tikus wistar serta keturunannya, seperti yang di
tunjukkan dari segi biokimia dan data histologikal. Oleh itu, rawatan ini boleh di
gunakan bersama dengan ubatan anti-tuberkulosis, rifampisin. Di sampling itu,
penyelidikan ekspresi gen juga menunjukkan gen terbabit samaada ‘upregulated’
mahupun ‘downregulated’ berpunca dari kesan pengambilan ubat ini. Walau
bagaimanapuan, ianya akan kembali kepada perubahan lipatan yang normal kesan
dari rawatan sel stem. Hal ini menunjukkan bahawa pengambilan sel stem
mesenkima diperolehi daripada sum-sum tulang menunjukkan aktiviti modulasi,
penjanaan semula serta aktiviti terapeutik terhadap kerosakkan pada organ hati dan
buah pinggang akibat rawatan menggunakan rifampisin dalam tempoh masa yang
lama dalam tikus wistar serta progeninya dapat dilihat kesannya dari segi penanda
aras biokimia, penilaian, histologi, penjumlahan sel serta kajian ekspresi gen.
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ACKNOWLEDGEMENTS
All praises are for Almighty ALLAH, the most Beneficent, ever Merciful, countless
thanks to Him, Lord of lords who guides us in darkness and helps in difficulties. And
all respects and regards to Holy prophet (peace be upon him) for enlightening our
conscience with the essence of faith in Allah, converging all his kindness and mercy
upon us. It is a great pleasure and honour for me to express my profound and cordial
gratitude to Dr. Suresh Kumar for his learned guidance, skilled advice and
sympathetic attitudes during the course of the work. All words in my knowledge just
fall to pay tribute to Dr. Mok Pooi ling, for her marvelous and splendid guidance,
winsome attitude, rewardless efforts and nice co-operation in the completion of the
work, I am grateful to Dr. Rukman Awang Hamat. I am also thankful to my team
members Sakinah Bt Maideensa Syed Gulam Rasul, Hiba, Sharmilah Kumari, Amira
and Poorani and to postgraduate students of medical microbiology and stem cell
research lab for their supports. I am also thankful to the technologists in the
Department of Medical Microbiology and Parasitology, Stem cell Research lab and
Haematology lab for their support during the work. I am also thankful to Federal
University Dutse for giving me the opportunity to pursue this programme. Lastly I
am also thankful to my beloved Mother (Maimunatu), my wife (Salma), my children
Maimunatu (Mama), Hafsat (Ummi), Mohammad Auwal (Abba), brothers and
sisters and friends at Department of Microbiology and Biotechnology, Federal
University Duste, for their encouragement during the research journey, May the God
Almighty reward you abundantly.
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This thesis was submitted to the Senate of the Universiti Putra Malaysia and has
been accepted as fulfilment of the requirement for the degree of Doctor of
Philosophy. The members of the Supervisory Committee were as follows:
Suresh Kumar Subbiah, PhD
Senior Lecturer
Faculty of Medicine and Health Sciences
Universiti Putra Malaysia
Chairperson
Mok Pooi Ling, PhD
Senior Lecturer
Faculty of Medicine and Health Sciences
Universiti Putra Malaysia
Member
Rukman Awang Hamat, PhD
Associate Professor
Faculty of Medicine and Health Sciences
Universiti Putra Malaysia
Member
ROBIAH BINTI YUNUS, PhD
Professor and Dean
School of Graduate Studies
Universiti Putra Malaysia
Date:
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Declaration by graduate student
I hereby confirm that:
• this thesis is my original work;
• quotations, illustrations and citations have been duly referenced;
• this thesis has not been submitted previously or concurrently for any other degree
at any institutions;
• intellectual property from the thesis and copyright of thesis are fully-owned by
Universiti Putra Malaysia, as according to the Universiti Putra Malaysia
(Research) Rules 2012;
• written permission must be obtained from supervisor and the office of Deputy
Vice-Chancellor (Research and innovation) before thesis is published (in the
form of written, printed or in electronic form) including books, journals,
modules, proceedings, popular writings, seminar papers, manuscripts, posters,
reports, lecture notes, learning modules or any other materials as stated in the
Universiti Putra Malaysia (Research) Rules 2012;
• there is no plagiarism or data falsification/fabrication in the thesis, and scholarly
integrity is upheld as according to the Universiti Putra Malaysia (Graduate
Studies) Rules 2003 (Revision 2012-2013) and the Universiti Putra Malaysia
(Research) Rules 2012. The thesis has undergone plagiarism detection software
Signature: Date:
Name and Matric No: Lawal Danjuma (GS43217)
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Declaration by Members of Supervisory Committee
This is to confirm that:
• the research conducted and the writing of this thesis was under our
supervision;
• supervision responsibilities as stated in the Universiti Putra Malaysia
(Graduate Studies) Rules 2003 (Revision 2012-2013) were adhered to.
Signature:
Name of Chairman
of Supervisory
Committee:
Dr. Suresh Kumar Subbiah
Signature:
Name of Member
of Supervisory
Committee:
Dr. Mok pooi Ling
Signature:
Name of Member
of Supervisory
Committee:
Dr. Rukman Awang Hamat
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TABLE OF CONTENTS
Page
ABSTRACT i
ABSTRAK iii
ACKNOWLEDGEMENTS v
APPROVAL vi
DECLARATION viii
LIST OF TABLES xv
LIST OF FIGURES xviii
LIST OF ABBREVIATIONS xxi
CHAPTER
1 INTRODUCTION 1 1.1 Background 1 1.2 Statement of the Problem 4 1.3 Justification for the Study 4
1.4 Hypothesis 4 1.5 General Objective 4 1.6 Research outlook 5
2 LITERATURE REVIEW 10
2.1 Tuberculosis 10 2.2 Drug Impacts on Liver 11
2.2.1 Structure and function of the liver 11 2.2.2 Overall views due to drug-induced liver injury 11
2.2.3 Extents of the Predicament 12 2.2.4 Origin and development of DILI 12 2.2.5 Liver Function Enzyme Quantification 12
2.2.6 Categories of DILI 13 2.2.7 Hepatic acclimatization 13
2.2.8 Drug-induced acute hepatitis or hepatocellular injury 13 2.2.9 Nonalcoholic fatty liver disease 13 2.2.10 Hepatitis due to granuloma 14
2.2.11 Cholestasis 14 2.3 DILI During Medication of Tatent TB Infection 14
2.3.1 Rifampicin 14
2.3.2 Processes of liver toxicity 15
2.3.3 Drug interfaces 15 2.3.4 Medical features of liver toxicity 15 2.3.5 General liver toxicity 16
2.4 Drug Impacts on Kidney 16 2.4.1 Kidney 16
2.4.2 Pathogenic Processes 17 2.4.2.1 Altered IntraGlomerular Hemodynamics 17
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2.4.2.2 Tubular Cell Toxicity 17
2.4.2.3 Inflammation 17 2.4.2.4 Crystal Nephropathy 18 2.4.2.5 Rhabdomyolysis 19
2.4.2.6 Thrombotic Microangiopathy 19 2.4.3 Rifampicin 19
2.5 Stem Cells and Infectious Disease 20 2.5.1 Variation in Expression of Surface Marker Antibodies
on Bone MarrowMesenchymal Stem Cell in Rats and Mice
as Compared with Human 21 2.5.2 Three major criteria of MSCs 25 2.5.3 Therapeutic Potential of MSCs 25
2.5.3.1 Competency to Move and Graft 26 2.5.3.2 Delineation or Differentiation 26
2.5.3.3 Production of Several Bioactive Particles 27 2.5.3.4 Immunomodulatory Roles of MSCs 28
2.6 Bone Marrow Derived Mesenchymal Stem Cells and their roles
in organ Repair 29 2.6.1 BMMSCs and its Role in Kidney Treatment 29 2.6.2 BMMSCs and its Role in Liver Treatment of Diseases 29
2.7 Clinical Usage of Bone marrow Derived Stem cells 30 2.8 MSCs for liver Disorder 31
2.8.1 Liver redevelopment or regeneration 31
2.8.2 Cellular processes associated with liver redevelopment 32 2.8.3 Cell based medication for liver redevelopment 33
2.8.4 Concise Clinical Tests with BMMSCs in human with
Liver Disorder 33
2.9 MSCs for the Treatement of kidney Disorders 35 2.9.1 Acute Kidney Disorder 35
2.9.2 Kidney Replacement or Transplantation 37 2.9.3 Chronic Kidney Disorder 38 2.9.4 Preclinical Trials of Chronic Kidney Disorder Treatment
using BMSCs 40 2.9.5 Clinical Tests Involing Mesenchymal Stem Cells for
Kidney Restoration 41 2.9.6 Paracrine Processes of BMSCs Treatment in Acute
renal failure (ARF) 42
2.10 Appropriate Animal Prototype for Tuberculosis Investigation 43 2.11 Molecular Investigations of Liver Damage due to Anti-
tuberculosis Drug Treatment 44
2.12 Molecular Investigation of Kidney Damage due to Anti-
tuberculosis Drug Treatment 47
3 ISOLATION, EXPANSION AND CHARACTERIZATION OF
BONE MARROW DERIVED MESENCHYMAL STEM CELLS
FROM WISTAR RAT 48
3.1 Introduction 48 3.2 Materials and method 48
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3.2.1 Isolation of Bone Marrow Derived Mesenchymal Stem
cells from wistar Rat 48 3.2.2 Procedure 48
3.3 Expansion and Passaging of bone marrow derived mesenchymal
stem cells 49 3.3.1 Procedure 49
3.4 Cell Counting 50 3.4.1 Preparing hemocytometer 50 3.4.2 Preparing cell suspension 50
3.4.3 Counting 50 3.5 Cryopreservation of Mesenchymal Stem Cells 51
3.5.1 Media and Solutions 51 3.5.2 Procedure 51
3.6 Thawing of Cryopreserved Cells 51
3.7 Immunophenotyping Characterization 52 3.8 Tri-lineage Differentiation and staining 52
3.8.1 Preparation of Reagents 52 3.8.2 Preparation of Osteogenesis Induction Medium: 53 3.8.3 Preparation of Mesenchymal Stem Cell Expansion Medium 53 3.8.4 Osteogenesis Differentiation (for 24-well tissue culture
plates) 54 3.8.5 Cell Plating 54 3.8.6 Alizarin Red Staining Protocol 54
3.8.7 Preparation of Reagents 54 3.8.8 Preparation of Adipogenesis Induction Medium: 55
3.8.9 Preparation of Adipogenesis Maintainace Medium: 55 3.8.10 Preparation of Mesenchymal Stem Cell Expansion Medium 56
3.8.11 Adipogenesis Differentiation 56 3.8.12 Oil red O staining protocol: 57
3.8.13 Preparation of Chondrogenic Differentiation (CD) Medium 57 3.8.14 Chondrogenesis differentiation 58 3.8.15 Alcian blue staining 58
3.9 Results 58 3.9.1 Isolation, expansion and characterization of bone
marrow derived mesenchymal stem cells from wistar rat 58 3.9.2 Isolated bone marrow derived mesenchymal stem cells
from wistar rat 59
3.9.3 Immunophenotyping characterization of bone marrow
derived mesenchymal stem cells from wistar rat 60
3.9.4 Osteoblast detection in bone marrow derived
mesenchymal stem cells 61
3.9.5 Adipocyte detection in bone marrow derived
mesenchymal stem cell 61 3.9.6 Chondrogenic detection in bone marrow
derived mesenchymal stem cell 62 3.10 Discussion 63
3.11 Conclusion 63
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4 EFFECTIVENESS OF TRANSPLANTED BONE MARROW
DERIVED MESENCHYMAL STEM CELLS IN AVERTING
ORGAN DAMAGE DUE TO RIFAMPICIN TREATMENT 65 4.1 Introduction 65
4.2 Materials and method 65 4.2.1 Sample Size Calculation for Animal Studies 65 4.2.2 Grouping and Treatment of Animal 66 4.2.3 Administration of Rifampicin 67 4.2.4 MSCs infusion (Administration of MSCs) 67
4.2.5 Collection of serum 67 4.2.6 Organ extraction 68 4.2.7 Histological Analysis 68 4.2.8 Statistical Analysis 68
4.3 Results 68
4.3.1 Blood biochemistry Parameters of Rat and their progeny
after 4-month treatment with rifampicin and rifampicin
plus bone marrow derived mesenchymal stem cells 68 4.3.2 Histological examination of kidney tissue from the parent
rats 81 4.3.3 Histological examination of kidney tissue from progeny
rats 84 4.3.4 Histological examination of liver tissue from the parent rats 86 4.3.5 Histological examination of liver tissue from progeny rats 88
4.4 Discussion 96 4.5 Conclusion 102
5 EFFECTIVENESS OF TRANSPLANTED BONE MARROW
DERIVED MESENCHYMAL STEM CELLS IN CORRECTING
DYSREGULATED GENES DUE TO RIFAMPICIN
TREATMENT 103 5.1 Introduction 103 5.2 Materials and method 103
5.2.1 Total RNA Extraction and RNA integrity number
(RIN) Assessment 103
5.2.2 Library Preparation and Quality Checking (QC) 104 5.2.3 mRNA Isolation, Fragmentation and Priming Starting
with Total RNA 104
5.2.4 Preparation of First Strand Reaction Buffer and
Random Primer Mix 105
5.2.5 First Strand cDNA Synthesis 105
5.2.6 Second Strand cDNA Synthesis 106
5.2.7 Purifying the Double-stranded cDNA Using 1.8X
Agencourt AMPure XP Beads 106 5.2.8 End Prep of cDNA Library 107 5.2.9 Adaptor Ligation 107 5.2.10 Purifying the Ligation Reaction Using AMPure XP Beads 108
5.2.11 PCR Library Enrichment 109 5.2.12 Purification of the PCR Reaction using Agencourt
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AMPure XP Beads 109
5.2.13 Assessing library quantity and quality on Qubit
and Bioanalyzer (Qubit Fluorometer 2.0 & Agilent 2100
High Sensitivity Chip) 110
5.3 Library Sequencing 110 5.4 Gene Expression Analysis (Transcriptomic construction or
Read mapping & quantification) 110 5.5 Results 111
5.5.1 Mapping and Annotation 111
5.5.2 The Number of Expressed Genes 111 5.5.3 Functions of some new genes expressed in the liver
and kidney of rifampicin treated and rifampicin plus stem
cells treated rats and their progenies 130 5.5.4 Analysis of Differential Gene Expression 139
5.6 Discussion 173 5.7 Conclusion 180
6 SUMMARY, GENERAL CONCLUSION AND
RECOMMENDATIONS FOR FUTURE RESEARCH 181
REFERENCES 182 APPENDICES 219 BIODATA OF STUDENT 424
LIST OF PUBLICATIONS 425
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LIST OF TABLES
Table Page
2.1 Variation in Expression of Immunophenotyping Surface Markers
Antibodies on Bone MarrowMesenchymal Stem Cell in Rats and
Mice as Compared with Human 22
2.2 Clinical Test of MSCs Based Treatment as Categorized by Disease
Kinds 31
2.3 Clinical Tests of MSC as Categorised by Phase 31
3.1 Osteogenesis Induction Medium Preparation 53
3.2 Mesenchymal Stem Cell Expansion Medium Preparation 53
3.3 Adipogenesis Induction Medium Preparation 55
3.4 Adipogenesis Maintenance Medium Preparation 55
3.5 Mesenchymal Stem Cell Expansion Medium Preparation 56
3.6 Differentiation Schedule for Adipogenesis induction 57
3.7 Chondrogenic Differentiation (CD) Medium Preparation 57
4.1 Mean ± Blood biochemistry Parameters of Rat and their progeny after
4-month treatment with rifampicin and rifampicin plus bone marrow
derived mesenchymal stem cells 70
4.2 Mean ± Quantitative histopathological analysis of kidney changes due
to rifampicin treatment and rifampicin plus bone marrow derived
mesenchymal stem cells 82
4.3 Mean ± Quantitative histopathological analysis of liver changes due to
rifampicin treatment and rifampicin with bone marrow derived
mesenchymal stem cells 87
5.1 First Strand Reaction Buffer and Random Primer Mix Preparation 105
5.2 Synthesis of First Strand cDNA 106
5.3 Synthesis of Second Strand cDNA 106
5.4 cDNA Library End Prep 107
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5.5 Adaptor Ligation 108
5.6 Enrichment of PCR Library 109
5.7 PCR cycling conditions for Library Enrichment 109
5.8 Number of new genes from Liver of rifampicin treated adult rats 112
5.9 Number of new genes from Liver of rifampicin plus stem cells treated
adult rats 112
5.10 Number of new genes from Liver progeny of rifampicin treated rats 113
5.11 Number of new genes from Liver progeny of rifampicin plus stem
cells treated rats 115
5.12 Number of genes expressed in control progeny group but not
expressed in progeny of rifampicin treated Liver group 116
5.13 Number of genes expressed in control progeny group but not
expressed in progeny of rifampicin plus stem cells treated Liver group 118
5.14 Number of new genes from kidney of rifampicin treated adult rats 119
5.15 Number of new genes from kidney of rifampicin plus stem cells
treated adult rats 119
5.16 Number of new genes from kidney progeny of rifampicin treated rats 120
5.17 Number of new genes from kidney progeny of rifampicin plus stem
cells treated rats 121
5.18 Number of gene expressed in control group but not expressed in
rifampicin treated kidney rats 122
5.19 Number of gene expressed in control group but not expressed in
rifampicin plus stem cells treated kidney rats 122
5.20 Number of genes expressed in control progeny group but not
expressed in progeny of rifampicin treated kidney group 122
5.21 Number of genes expressed in control progeny group but not
expressed in progeny of rifampicin plus stem cells treated kidney
group 126
5.22 Statistical power to detect differential expression varies with effect
size, sequencing dept and number of replicates 139
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5.23 Shows the expression levels of some fifty up-regulated genes between
male adult rifampicin treated liver and also male adult rifampicin plus
stem cells treated liver samples 140
5.24 Shows the expression levels of some fifty down-regulated genes
between male adult rifampicin treated liver and also male adult
rifampicin plus stem cells treated liver samples 143
5.25 Shows the expression levels of some fifty up-regulated genes between
male progeny rifampicin treated and also male progeny rifampicin
plus stem cells treated liver samples 146
5.26 Shows the expression levels of some fifty down-regulated genes
between male progeny rifampicin treated and also male progeny
rifampicin plus stem cells treated liver samples 149
5.27 Gene expression changes between rifampicin and rifampicin plus stem
cells treated adult kidney 152
5.28 Gene expression changes between rifampicin and rifampicin plus stem
cell treated progeny kidney 154
5.29 Gene expression changes between rifampicin and rifampicin plus stem
cell treated adult liver 157
5.30 Gene expression changes between rifampicin and rifampicin plus stem
cells treated progeny liver 159
5.31 Shows the expression levels of some fifty up-regulated genes between
male adult rifampicin treated kidney and also male adult rifampicin
plus stem cells treated kidney samples 162
5.32 Shows the expression levels of some fifty down-regulated genes
between male adult rifampicin treated kidney samples and also male
adult rifampicin plus stem cells treated kidney samples 165
5.33 Shows the expression levels of some fifty up-regulated genes between
male progeny rifampicin treated kidney samples and also male
progeny rifampicin plus stem cells treated kidney samples 168
5.34 Shows the heatmap expression levels of some fifty down-regulated
genes between male progeny rifampicin treated kidney samples and
also male progeny rifampicin plus stem cells treated kidney samples 171
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LIST OF FIGURES
Figure Page
1.1 Research outlook 6
1.2 Research outlook continued 7
1.3 Research outlook continued 8
1.4 Research outlook continued 9
3.1 Morphological features of bone marrow derived mesenchymal stem
cells 59
3.2 Immunophenotyping Characterization of bone marrow derived
mesenchymal stem cells 60
3.3 Osteoblast detection in bone marrow derived mesenchymal stem cell 61
3.4 Adipocyte detection in bone marrow derived mesenchymal stem cell 62
3.5 Chondrogenic detection in bone marrow derived mesenchymal stem 62
4.1 Mean±SD of the concentrations (U/L) of alanine aminotransferase 71
4.2 Mean±SD of the concentrations (U/L) of aspartate aminotransferase 72
4.3 Mean±SD of the concentrations (mg/dl) of total bilirubin 73
4.4 Mean±SD of the concentrations (g/dl) of total protein 74
4.5 Mean±SD of the concentrations (g/dl) of albumin 75
4.6 Mean±SD of the concentrations (mg/dl) of urea 76
4.7 Mean±SD of the concentrations (mg/dl) of creatinine 77
4.8 Mean±SD of the concentrations (mg/dl) of triglyceride 78
4.9 Mean±SD of the concentrations (mg/dl) of cholesterol 79
4.10 Mean±SD of the concentrations (mg/dl) of low density lipolipid
cholesterol 80
4.11 Mean±SD of the concentrations (mg/dl) of high density lipolipid
cholesterol 81
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4.12 Histological examination of kidney tissue from the parent rats 83
4.13 Histological examination of kidney tissue from progeny rats 85
4.14 Mean glomeruli size of rats and their progenies 86
4.15 Histological examination of liver tissue from the parent rats 88
4.16 Histological examination of liver tissue from progeny rats 90
4.17 Mean hepatocyte size of rats and their progenies 91
4.18 Mean hepatocyte count of rats and their progenies 92
4.19 Mean bi-nucleated hepatocyte count of rats and their progenies 93
4.20 Mean Kupffer count of rats and their progenies 94
4.21 Mean pycnotic nuclei count of rats and their progenies 95
4.22 Mean vacuolated hepatocyte count of rats and their progenies 96
5.1 Gene expression differences of adult rat kidney trancriptomic profile 135
5.2 Gene expression differences of progeny rat kidney trancriptomic
profile 136
5.3 Gene expression differences of adult rat liver trancriptomic profile 137
5.4 Gene expression differences of progeny rat liver trancriptomic 138
5.5 The heatmap showing the expression levels of the first 50 upregulated
genes in adult liver 142
5.6 The heatmap showing the expression levels of the first 50
downregulated genes in adult liver 145
5.7 The heatmap showing the expression levels of the first 50 upregulated
genes in progeny 148
5.8 The heatmap showing the expression levels of the first 50
downregulated genes in progeny liver 151
5.9 The heatmap showing the expression levels of the first 50 upregulated
genes in adult kidney 164
5.10 The heatmap showing the expression levels of the first 50
downregulated genes in adult kidney 167
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5.11 The heatmap showing the expression levels of the first 50 upregulated
genes in progeny kidney 170
5.12 The heatmap showing the expression levels of the first 50
downregulated genes in progeny kidney 173
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LIST OF ABBREVIATIONS
% Percentage
≤ Less than or equal
≥ Greater than or equal
µg Microgram
µL Micro-litre
µm Micrometer
µM Micromolar
A/G Albumin/Globulin
ACE Angiotensin-converting enzyme
AFB1 Aflatoxin B1
AGVHD Acute graft-versus-host disease
AIH Autoimmune hepatitis
AKI Acute kidney injury
ALD Adrenoleukodystrophy
ALF Acute liver failure
ALT Alanine amino transferase
ANOVA Analysis of variance
AP Acute pancreatitis
ARBs Angiotensin receptor blockers
ARF Acute renal failure
AST Aspatate amino transferase
BCL2 B-cell lymphoma 2
BDEC Bile duct epithelial cells
BDNF Brain-derived neurotrophic factor
BFGF Basic fibroblast growth factor
BM Bone marrow
BM-MNCs Bone marrow mononuclear cells
BM-MSC Bone marrow derived mesenchymal stem cells
Bw Between
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C57BL/6 Black 6 mouse from Charles River Laboratories
CCl4 Carbon tetrachloride
CCR2 C-C chemokine receptor type 2
CCR3 C-C chemokine receptor type 3
CCR4 C-C chemokine receptor type 4
CCR5 C-C chemokine receptor type 5
CD Cluster of differentiation
CD Crohn’s disease
CGVHD Chronic graft-versus-host disease
CKD Chronic kidney disease
CLD Chronic liver disease
Cm2 Centimeter square
CPS Calcium phosphosilicate
CXCR4 Chemokine receptor type 4
DCs Dendritic cells
DEG Differentially expressed genes
DILI Drug-induced liver injury
DMEM Dulbecco's Modified Eagle's Medium
DMSO Dimethyl sulfoxide
DPBS Dulbecco's phosphate-buffered saline
ECM Extracellular molecule
EDTA Ethylenediaminetetraacetic acid
EGF Epidermal growth factor
EPO Erythropoietin
ESC Embryonic stem cell
ESC Embryonic stem cells
F1 generation Filial generation
FBS Fetal bovine serum
FDA Food and Drug Administration
FDR False discovery rate
FGF-4 Fibroblast growth factor 4
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FHF Fulminant hepatic failure
FHF Fulminant hepatic failure
Fig Figure
Foxp3 Forkhead box protein P3
FPKM Fragments Per Kilobase of transcript per Million
mapped reads
G Gram
G/dl Gram/deciliter
Ga1N Galactosamine induced
GFR Glomerular filteration rate
GO Gene ontology
HBV Hepatitis B virus
HCC Hepatocellular carcinoma
HCl Hydrochloric acid
HCV Hepatitis C virus
HDL High density lipolipid
HDL High density lipolipid
HGF Hepatocyte growth
HIV Human immunodeficiency virus
HLA Human leukocyte antigen
HLA-DR Human Leukocyte Antigen – antigen D Related
HLA-G5 Human leukocyte antigen G isoform
Hrs hour
HSC Hepatic stallate cells
I/R Ischemia-reperfusion
IACUC Institutional Animal Care and Used Committee
IGF-1 Insulin-like growth factor 1
IHC Immunohistochemistry
IL-10 Interleukin-10
IL-12 Interleukin-12
INR International normalize ratio
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IPF Idiopathic pulmonary fibrosis
IPSC Induced pluripotent stem cells
IU/L International unit per litre
KC Kupffer cells
KEGG Kyoto encyclopedia of genes and genomes
Kg Kilogram
LDL Low density lipolipid
LDL Low density lipolipid
LFT’s Liver function tests
LL 37 Cathelicidin antimicrobial peptide
LTBI Latent TB Infection
LVEF Left ventricular ejection fraction
M Molar
MCP-1 Monocyte chemo-attractant protein-1
MDR/RR-TB Multidrug-resistant TB/ Rifampicin-resistance TB
MDR-TR Multidrug-resistant TB
Mg Milligram
Mg/dl Milligram/deciliter
MI Myocardial infarction
Min Minute
ML Milliter
mM Millimolar
MMP3 Matrix metalloproteinase-3
MMP9 Matrix metalloproteinase-9
mRNA Messenger ribonucleic acid
MSC Mesenchymal stem cell
Mtb Mycobacterium tuberculosis
MR Male rifampicin
MC Male control
MRSC Male rifampicin plus stem cell
MDC Madin-Darby canine kidney epithelial cell
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N Normality
NASH Nonalcoholic steatohepatitis
NCBI National Center for Biotechnology Information
NGS Next generation sequencing
NHPTK Human proximal tubular eprthelial cell
NK cell Natural killer cell
Nm Nanomolar
NSAIDs Non-steroidal anti-inflammatory drugs
oC Degree centigrade
OLT Orthotopic liver transplantation
PBC Primary biliary cirrhosis
PBS Phosphate buffered saline
PBSCT Peripheral blood stem cell transplantation
PCI Percutaneous coronary intervention
PCR Polymerase chain reaction
PDGF Platelet-derived growth factor
Pen-Strep Penicillin-streptomycin
PGE2 Prostaglandin-E2
PH Partial hepatectomy
PIGF Placenta growth factor
QC Quality checking
RNA Ribonucleic acid
RPM Revolution per minute
RR-TB Rifampicin-resistance TB
SD Standard deviation
SEC Sinusoidal endothelial cells
SGOT Serum glutamic oxaloacetic transaminase
SGPT Serum glutamate transaminase
STAT3 Signal transducer and activator of transcription 3
STAT3 Signal transducer and activator of transcription 3
STZ Streptozocin
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TB Tuberculosis
TCA Tricarboxylic acid
TE Tris EDTA
TGFα Transforming growth factorα
TGFβ1 Transforming growth factorβ-1
TNF tumor necrosis factor
U/L Units per litre
ULN Upper limit of normal
UPM Universiti Putra Malaysia
VEGF Endothelial growth factor
VEGF vascular endothelial growth factor
WHO World health organization
XDR-TB Extensive drug-resistance
ZDF Zucker diabetic fatty
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CHAPTER 1
1 INTRODUCTION
1.1 Background
Infections caused by bacteria have become a main health predicament in recent
years, because some of the bacterial infections are very difficult to eradicate,
consequently leading to an increase in morbidity and mortality in both economically
advanced and less advanced countries (Samuel et al. 2011). Particularly, the disease
tuberculosis kills nearly 2 million people globally annually (Gursimrat et al. 2011,
Philippe et al. 2006). Although antibiotics clears off infection and improve the
health, for some infections, the courses of medication preceded up to several months
and do not completely eradicate the infection, which often reoccurs years or decades
after the initial treatment (Das et al. 2013).
Mycobacterium tuberculosis has a very puzzling method of pathogenesis. It seems to
defy logic by actually using macrophages, the front line defenses of the human
immune system, as a safe heaven for its reproduction. Also the bacteria can still
persist in secured niches like bone marrow mesenchymal stem cells, and then
reactivate the disease (Menzies, Al Jahdali and Otaibi, 2011), leading to therapeutic
failure (WHO, 2014). Furthermore, the bacteria has a spectacular ability of long term
persistence despite vigorous host immunity and prolonged therapy (Lonnroth and
Raviglione, 2008; Lilleback et al; 2003). The spread and bordened of tuberculosis
(TB) is one of the most present emergencies currently facing the human population,
with the untreated cases and multidrug resistant strains often leading to mortality.
Although frequencies of infection are decreasing with the introduction of antibiotics,
TB infection is once more increasing and currently 26% (2.7 million) of all
avoidable deaths in the world are due to TB (brown.edu, 2000). The global burden of
TB drug resistance as at 2015, were estimated at 480,000 new cases of multidrug-
resistant TB (MDR-TB) and additional 100,000 people with rifampicin-resistance
TB(RR-TB) who were also newly eligible for MDR-TB treatment. Drug resistance
surveillance data show that 3.9% of new and 21% of previously treated TB cases
was estimated to have had rifampicin-or multidrug-resistant tuberculosis (MDR/RR-
TB) in 2015. As in 2014, MDR-TB accounts for 3.3% of new TB cases. MDR/RR-
TB caused 250,000 deaths in 2015. Most cases and deaths occurred in Asia. About
9.5% of MDR-TB cases have additional drug-resistance, extensive drug-resistance
TB (XDR-TB). To date, 117 countries worldwide have at least one XDR-TB cases
(WHO, 2016).
TB is spread through breathing of airborne Mycobacterium tuberculosis cells which
multiply in macrophages and within the large cystic tubercles they form-liquified
caseous tissue surrounded by infected macrophages (Bichun et al., 1996). These
reduce regular functioning of the lungs, leading to its rupture to spread the pathogen.
In order to achieve efficient cure of tuberculosis, the treatment normally last for a
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period of 6-9months. These prolong rifampicin treatment due to Mycobacterium
tuberculosis infection can leads to toxic effect and some vital organ damage.
Rifampicin being a bactericidal antibiotic drug in rifamycin group, semisynthetic
that originated from Streptomyces species, is the most efficient, effective and
considered a first line drug in the management and treatment of tuberculosis
worldwide (Eminzade et al., 2008), but its normally comes with several
toxicological side effects. Possible complications of tuberculosis and prolonged
rifampicin treatment include liver and kidney damage; these conditions can lead to
reduced efficiency of the affected organs and consequently lead to other diseases.
Rifampicin do generates a lot of morphological changes in the liver by its metabolic
activity, since the liver serves as the detoxification point of the drug (Santhosh et al.,
2007). There was a remarkable increase in lipid peroxidation in a four weeks
medication using rifampicin (20mg/kg) intraperitoneally as reported by Upadhyay et
al., 2007. An extraordinary elevation in triglycerides and cholesterol levels in rats
treated with rifampicin at a dose of 250mg/kg/day, for a period of one month was
noticed (Tasduq et al., 2007). In 2006, Santhosh et al, reported a remarkable
elevation in triglycerides, cholesterol and free fatty acids in serum sample of rats that
received (200mg rifampicin + 200mg isoniazid) for a period of one month. Pal et al.
(2008) reported a small decrease in the level high density lipolipid (HDL)
cholesterol with concurrent increase in low density lipolipid (LDL) cholesterol level,
while a remarkable elevation in serum sample of aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) levels due to anti-TB medication was reported
by Rana et al., 2010.
Increase in levels of both AST and ALT were reported after treating patients
(Balamurugan et al., 2009) and mice with rifampicin (Upadhyay et al., 2007). A
decrease in albumin level was reported in tuberculosis patients and healthy
volunteers after studying the pharmacokinetics of the drug, because rifampicin
usually binds to albumin only (Rafiq et al., 2010). A reduction in total protein and
albumin levels in rat serum was noted after treating them with anti-TB drugs
(Santhosh et al., 2007 and Eminzade et al., 2008). Treatment of rats with rifampicin
at a dose of 10mg/kg/day for a period of 3-weeks revealed a remarkable reduction of
total bilirubin in the serum (Balamurugan et al., 2009). A remarkable rise in the
serum bilirubin, urea, and creatinine levels was reported in patients treated with
isoniazid (300mg/day), rifampicin (600mg/day), pyrazinamide (2g/day), and
ethanbutol (1g/day) for a period of eight months (Yanardag et al., 2005).
In a similar experiment, a remarkable rise in serum bilirubin and a reduction in
serum urea levels were recorded in rats treated with isoniazid and rifampicin 200mg
each/kg bw/day for a period of one month. Also an extraordinary elevation in serum
bilirubin and urea was reported, but with no meaningful changes in creatinine level
of rats that received 250mg/kg of rifampicin for a period of 4-weeks. The liver and
kidney toxicity of rifampicin treatment have also been reported by some researchers
like Awodele et al., 2010 and Rehka et al., 2005. Shabana et al. (2012) in a similar
experiment reported a remarkable elevation in total cholesterol, triglycerides and
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LDL-cholesterol levels and with a reduction in HDL-cholesterol level. Also an
elevation in AST, ALT, bilirubin and urea was reported by Shabana et al., 2012,
with a drastic reduction in total protein, albumin and alpha 1-globulin and no
remarkable changes in globulin fractions (alpha 2-, beta- and gamma-globulin) and
albumin/globulin ratio (A/G) as well as creatinine level (Shabana et al., 2012).
Histopathological changes in liver like necrosis of hepatocytes, cytoplasmic
vacuolation, and distended sinusoids, lymphatic aggregations, while kidney damages
like glomeruli increased, mesangial matrix expansion and renal tubules regeneration
were also reported (Shabana et al., 2012) in albino rats that were treated with
rifampicin for a period of 4-weeks at a dose of 200mg/kg body weight/day via oral
gastric tubes (Santhosh et al., 2007). A lot of histopathological changes like; isolated
steatosis (through varying degrees of portal inflammation with neutrophils or
mononuclear infiltrate) to confluent necrosis in some patients that showed abnormal
liver function test within six weeks of rifampicin therapy were also reported
(Scheuer et al., 1974).
Also diffuse microvesicular fatty infilteration accompanied with mild portal triatidis
was reported in rats that received isoniazid treatment at a dose of 50mg/kg/day and
rifampicin 100mg/kg/day for a period of one week (Kalra et al., 2007). Furthermore,
combination of anti-TB drug: (100mg/kg/day + 50mg/kg/day + 100mg/kg/day of
pyrazinamide) once daily for a period of 3 months revealed membrane disintegration
and loss of the polyhedral structure in the liver, and also other abnormalities such as
necrosis, macro vesicular steatosis and inflammation were also reported. Prolong
rifampicin therapy can also cause hemolysis and subsequently acute kidney failure,
can also leads to interstitial nephritis (which is due to its direct toxic effect) and is
seen as part of pan-nephropathy (Lee, 1978). Renal lesion were seen, that are due to
the formation of immune complexes that were detected on capillary glomerular
basement membranes using the immunofluorescent and electron microscopy.
Deterioration in kidney activity seems to be acute in the case of reintroduction of
rifampicin (Covic et al., 1998).
The advancement in science and technology has led to the invention of stem cell, a
new concept for the regeneration of damaged tissues. Several reports on the success
of stem cell therapy and its practical application in regeneration of damaged tissues
prompted us to perform a preclinical study to determine its potential in managing the
tissue damages caused by prolonged rifampicin treatment. Stem cell therapy as a
regenerative form of medicine can be used in conjunction with the rifampicin to
manage the toxicological side effects and also to avert the architectural organ
damage. Bone marrow derived mesenchymal stem cells can differentiate into so
many cell types including the liver and kidney and there are ample evidences
indicating tissue repair or regeneration by differentiation of stem cells into the
damaged cell types. Thus, this present study will address the genes dysregulatory
conflict due rifampicin treatment and it is our hope that the damaged organs (kidney
and liver) due to prolong rifampicin treatment will be cured after receiving the stem
cell therapy.
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1.2 Statement of the Problem
i. Rifampicin treatment due to Mycobacterium tuberculosis infection can caused
damage to some vital, such as liver and kidney. This can lead to acute liver
and kidney failure. Stem cell therapy as a regenerative form of medicine
using bone marrow derived mesenchymal stem cells can be used in
conjunction with the rifampicin to avert the organ damage and thereby
rescuing the affected organs.
1.3 Justification for the Study
i. Prolong rifampicin therapy due to tuberculosis and the toxicity of the drug;
coupled with the proportionate risk of kidney/liver malfunction has stress the
need for a new interventional approach. Intravenous administration of bone
marrow derived mesenchymal stem cells along with rifampicin can yield a
promising result. Because hepatocytes and renal cells growth factors that are
released by mesenchymal stem cells have multiple function of antiapoptotic
stimulation and antioxidant actions, as such can neutralized the toxicological
impacts of the drug. Also the ability of the transplanted MSCs to differentiate
into liver and kidney cells can help in the organ regeneration as well.
1.4 Hypothesis
i. Rifampicin treatment due to tuberculosis infection can cause damage to liver and
kidney and this can lead to alteration in the genetic pathways and also in the
chromosomes.
ii. These disorders may be carried to the next generations. So in our hypothesis
stem cell therapy can avert the organ damage caused by the rifampicin treatment
and may correct the dysregulated genes.
1.5 General Objective
To determine the therapeutic potentials of bone marrow derived mesenchymal
stem cells in averting organ damage due to rifampicin treatment in wistar rats
and their progenies.
Specific Objectives
i. To isolate, expand and characterized bone derived mesenchymal stem cells
from wistar rat.
ii. To determine the effectiveness of transplanted bone marrow derived
mesenchymal stem cells in averting organ damage due to rifampicin
treatment.
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iii. To detect any differentially expressed genes (dysregulated genes) due to
prolong rifampicin treatment on the wistar rats and their progenies using next
generation sequence technique.
iv. To determine the effectiveness of transplanted bone marrow derived
mesenchymal stem cells in correcting the differentially expressed genes
(dysregulated genes) on Wistar rats and their progenies using next generation
sequence technique.
1.6 Research outlook
The research work involving animal experimentation is summarized into four parts
(Fig. 1.1, 1.2, 1.3, 1.4). The first part involves the oral administration of therapeutic
doses of rifampicin (9 mg/kg/day) to both male and female wistar rats while the
control received normal saline for the period of three consecutive months. The
second part involves breeding of the rats that were previously treated with rifampicin
(while the treatment continue during the breeding), after their delivery, blood, kidney
and liver samples were collected from the parents and their progenies for
biochemistry analysis, histology and RNA (Ribonucleic acid) extraction from liver
and kidney for next generation sequencing. The third part involves oral
administration of therapeutic doses of rifampicin 9mg/kg/day for 3-months and
intravenous administration of bone marrow derived mesenchymal stem cells, 100μl
2.5 x 105 cells twice/month for 3-months to both male and female wistar rat. The
fourth part involves breeding of the rats that were previously treated with rifampicin
and MSCs (while the treatment continue during the breeding), after their delivery,
blood, kidney and liver samples were collected from the parents and their progenies
for biochemistry analysis, histology and RNA extraction form liver and kidney for
next generation sequencing.
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