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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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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


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



Member

Rukman Awang Hamat, PhD

Associate Professor



Member

ROBIAH BINTI YUNUS, PhD

Professor and Dean

School of Graduate Studies


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


4.3 Mean ± Quantitative histopathological analysis of liver changes due to

rifampicin treatment and rifampicin with bone marrow derived


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


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


expressed in progeny of rifampicin treated kidney group 122


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


male progeny rifampicin treated and also male progeny rifampicin

plus stem cells treated liver samples 146


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


cell treated progeny kidney 154


cell treated adult liver 157


cells treated progeny liver 159


male adult rifampicin treated kidney and also male adult rifampicin

plus stem cells treated kidney samples 162


between male adult rifampicin treated kidney samples and also male

adult rifampicin plus stem cells treated kidney samples 165


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



3.1 Morphological features of bone marrow derived mesenchymal stem

cells 59

3.2 Immunophenotyping Characterization of bone marrow derived


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


genes in progeny 148


downregulated genes in progeny liver 151


genes in adult kidney 164


downregulated genes in adult kidney 167

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genes in progeny kidney 170


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




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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Figure 1.1 : Research outlook.

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Figure 1.2 : Research outlook continued.

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