Title Page
ABSTRACT
Contents
LIST OF ABBREVIATION 15
CHAPTER 1. Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation 19
INTRODUCTION 20
MATERIALS AND METHODS 22
RESULTS 27
DISCUSSION 66
CHAPTER 2. A Preclinical Study of Human Embryonic Stem Cell Derived Mesenchymal Stem cells for Treating Detrusor Underactivity by Chronic Bladder Ischemia 71
INTRODUCTION 72
MATERIALS AND METHODS 73
RESULTS 76
DISCUSSION 96
REFERENCE 100
Abstract in Korean 112
Chapter 1 12
Figure 1-1. AA2G priming activates ATF2 and NRF2 in human MSCs 29
Figure 1-2. Crosstalk between the ATF2 and NRF2 pathways in AA2G-primed MSCs 32
Figure 1-3. Real-time live-cell GSH recovery capacity assay 34
Figure 1-4. ATF2 is critical for maintaining the core functions of hES-MSCs 38
Figure 1-5. ATF2-silenced hUC-MSCs display defective therapeutic functions 39
Figure 1-6. ATF2 ectopic expression enhanced PDGF-responsive chemotaxis in hES- and hUC-MSCs 41
Figure 1-7. ATF2 overexpression increased pro-angiogenic and anti-inflammatory capacities in hES- and hUC-MSCs 42
Figure 1-8. GSH dynamics play a role in ATF2-dependent MSC functionality 44
Figure 1-9. ATF2 silencing significantly impaired beneficial effects of the PFO procedure in hES- and hUC-MSCs 45
Figure 1-10. Role of ATF2 in the beneficial effects of the PFO procedure 46
Figure 1-11. Role of ATF2 in the improved anti-inflammatory activity by the PFO procedure 48
Figure 1-12. In vivo scheme for asthma induction and administration of MSCs 51
Figure 1-13. Severe inflammation in bronchial and vascular lung tissues of OVA-sensitized asthmatic mice 52
Figure 1-14. Increased cellularity and immune cells in OVA-induced asthmatic mice 53
Figure 1-15. Impaired beneficial effects of shATF2-expressing hUC-MSCs in Th2 immune response mediators of asthmatic mice 54
Figure 1-16. Up-regulation of Th2-related genes and pro-inflammatory cytokines in asthmatic mice 55
Figure 1-17. Immunostaining analysis of engraftment and cellular properties of transplanted hUC-MSCs 56
Figure 1-18. Co-staining of SFTPC and hB2M for the engrafted cells in lung tissues 57
Figure 1-19. Inflammation in bronchial and vascular lung tissues of OVA-sensitized asthmatic mice administrated with ATF2 over-expression hES-MSCs 60
Figure 1-20. Decreased cellularity and immune cells in OVA-sensitized asthmatic mice administrated with ATF2 over-expression hES-MSCs 61
Figure 1-21. Immunostaining analysis of engraftment and cellular properties of transplanted OVA-sensitized hES-MSCs with ATF2 over-expression 62
Figure 1-22. Inflammation in bronchial and vascular lung tissues of OVA-sensitized asthmatic mice transplanted with ATF2 over-expression hUC-MSCs 63
Figure 1-23. Decreased cellularity and inflammatory cell in OVA-sensitized asthmatic mice transplanted with ATF2 over-expression hUC-MSCs 64
Figure 1-24. Immunostaining analysis of engraftment and cellular properties of transplanted OVA-sensitized hUC-MSCs with ATF2 over-expression 65
Chapter 2 14
Figure 2-1. M-MSC injection restored bladder function in DUA rat models 77
Figure 2-2. Repair of bladder contractility by M-MSC therapy 80
Figure 2-3. M-MSCs injection repaired histological injury in CBI bladders 82
Figure 2-4. M-MSC therapy protected the apoptotic response in CBI bladders 83
Figure 2-5. Cellular lineages of transplanted M-MSCs in the CBI bladders 85
Figure 2-6. M-MSCs injection stimulated angiogenesis in CBI bladders 87
Figure 2-7. Gene expression analysis revealed that M-MSCs 88
Figure 2-8. Expression of a subset of pro-angiogenic factors 89
Figure 2-9. Expression of HIF-1 signaling pathways 92
Figure 2-10. Characteristic changes in complement immune response, inflammation, and ion transport pathways in CBI bladders 93
Figure 2-11. Pathway maps revealed in networks related to chemical sensory perception in DUA and sham bladders 94
Figure 2-12. Cross-talk between VEGF and Angiopoietin 1 signaling pathways 95