成體間質幹細胞可藉由細胞間轉移粒線體以拯救粒線體功能缺陷的細胞。產後剩餘臍帶中的華通氏膠富含間質幹細胞，是一個方便且可大量取得幹細胞的來源。肌陣攣癲癇發作伴破碎紅纖維(MERRF)症候群是由於母系遺傳突變的粒線體基因而造成的疾病，患病者會表現出動作、聽力、視覺或是心肺功能等障礙。而本研究將欲探討華通氏膠間質幹細胞是否有能力傳遞粒線體病治療MERRF症候群細胞的粒線體生物產能缺失。首先，將粒線體基因喪失的ρ0細胞與華通氏膠間質幹細胞共同培養，發現粒線體及其基因組自華通氏膠間質幹細胞傳遞至ρ0細胞，並恢復其原本缺損的呼吸功能，藉此確定華通氏膠間質幹細胞具有傳遞粒線體並拯救粒線體功能缺失。接著，將MERRF病人粒線體融入ρ0細胞建立出MERRF融合細胞，該細胞展現出粒線體功能缺失。最後，本研究發現，華通氏膠間質幹細胞可傳遞粒線體至MERRF融合細胞，並改善粒線體功能。總結之，華通氏膠間質幹細胞可傳遞功能性粒線體進入MERRF細胞，並改善粒線體功能與生物能量產出。在臨床應用上，本研究結果具有發展新療法的潛力。

Adult mesenchymal stem cells (MSCs)-conducted mitochondrial transfer has been recently shown to rescue mitochondrial bioenergetics and prevent cell death caused by mitochondrial dysfunction. Wharton’s jelly-derived MSCs (WJMSCs) harvested from postpartum umbilical cords are an accessible and abundant source of stem cells. Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome is characterized by disorders in motor, hearing, visual and cardiac functions and is associated with maternally-inherited mutation in mitochondrial genome. This study aimed to determine the capability of WJMSCs to transfer healthy mitochondria and rescue impaired mitochondrial bioenergetics caused by MERRF. Firstly, mitochondrial DNA (mtDNA)-depleted ρ0 cells and cybrids harboring MERRF mtDNA were created to be cellular models of mitochondrial defects. Secondly, WJMSCs was shown to be able to transfer mitochondria to ρ0 cells and rescued impaired mitochondrial function, verifying the ability of WJMSCs in conducting intercellular mitochondrial transfer. Finally, mitochondrial transfer from WJSMCs to MERRF cybrid was revealed. MERRF cybrids receiving mitochondrial transfer present improved mitochondrial function and bioenergetics. Collectively, this study suggests that WJMSCs may serve as a potential therapeutic strategy for mitochondrial diseases through the donation of healthy mitochondria to cells with genetic mitochondrial defects.

誌謝 ii
中文摘要 iii
Abstract iv
List of Figures圖次 viii
List of Tables表次 x
Terminology: abbreviations and symbols xi
Chapter 1: Introduction 1
1.1 Mitochondrial Biology 1
1.1.1 Basic Constitutions and Functions of Mitochondria 1
1.1.2 Mitochondrial Dynamics 2
1.1.3 Intra- and Inter-cellular Mitochondrial Transfer 4
1.2 Mitochondrial Genetics 6
1.2.1 MtDNA Organization 6
1.2.2 MtDNA Replication and Transcription 6
1.2.3 Maternal Inheritance and Transmission of mtDNA 8
1.2.4 Mitochondrial Dynamics and mtDNA maintenance 9
1.2.5 Mitochondrial Diseases 10
1.2.6 Neuromuscular Disease Caused by MtDNA Mutation: Myoclonic Epilepsy and Ragged Red Fibers (MERRF) 11
1.3 Cellular Model of MtDNA Defect 13
1.3.1 mtDNA-depleted ρ0 cells 14
1.3.2 Cybrids harboring mtDNA mutation from patient 14
1.4 Therapeutic Mitochondrial Transfer of MSCs 15
1.5 Wharton’s jelly mesenchymal stem cells (WJMSCs) 17
1.5.1 General Features 17
1.5.2 Surface Markers 18
1.5.3 Immuomodulatory Property 18
1.5.4 Proliferation and Differentiation Features 18
1.5.5 Mitochondrial Transfer of WJMSCs is still unknown 19
1.6 The aims of this study 20
Chapter 2: Materials and Methods 21
2.1 Cell culture and creation of ρ0 cell and cybrid 21
2.2 Isolation, cultivation and identification of WJMSCs 21
2.3 Experimental procedures of co-culture and imaging (Chapter 4) 22
2.4 Experimental procedures of co-culture and imaging (Chapter 5) 23
2.5 MtDNA content assay and identification of mitochondrial genotypes 24
2.6 Flow cytometry assay 25
2.7 Western blot 25
2.8 Oxygen consumption rate (OCR) 25
2.9 ATP and lactate assay 26
2.10 Colony formation assay 26
2.11 Mitochondria-dependent viability test 27
2.12 Cellular motility assay 27
2.13 Mitochondrial morphology 28
2.14 Statistical analysis 28
Chapter 3: The establishment of mtDNA-depleted ρ0 cell and MERRF cybrid 29
3.1 General Introduction 29
3.2 The creation of mtDNA-depleted ρ0 cell 29
3.3 Cybrids harboring mt.8344A>G mutation from MERRF patient 33
3.4 Summary 36
Chapter 4: Mitochondrial Transfer from WJMSCs to ρ0 cells Rescue Mitochondrial Function 38
4.1 General Introduction 38
4.2 WJMSCs transferred mitochondria to rescue ρ0 cells 38
4.2.1 ρ0 cells obtained mitochondria from WJMSCs and acquired proliferative ability in pyruvate/uridine-free medium 38
4.2.2 WJMSCs replenish ρ0 cells with mtDNA to form chimeric ρ+Wcells 43
4.2.3 ρ+W cells which received mtDNA from WJMSCs exhibited respiratory capacity and ETC complex activity 48
4.2.4 Glycolysis-reliant ρ0 cells were adapted to OXPHOS-reliant ρ+W cells by WJMSCs 54
4.2.5 ρ+W cells demonstrated aerobic viability and attachment-free proliferation 56
4.2.6 Cellular motility blunted by inactive OXPHOS was rescued following WJMSC-mediated mitochondrial transfer 57
4.2.7 The improvement in mitochondrial function by the WJMSC-derived mitochondrial transfer could be stably sustained 60
4.3 Summary 62
Chapter 5: Mitochondrial Transfer from WJMSCs to MERRF cybrid cells Rescues Mitochondrial Function 64
5.1 General Introduction 64
5.2 WJMSCs transferred mitochondria to rescue MERRF cybrids 64
5.2.1 Mitochondria and mtDNA from WJMSCs can be transferred to MERRF cybrids 64
5.2.2 MERRF cybrids recaptured normal mitochondrial biogenesis and morphology after recieving WJMSCs-derived mitochondrial transfer 69
5.2.3 Mitochondrial transfer from WJMSCs to MERRF cybrids improved bioenergetics 72
5.2.4 Proliferation and mitochondria-dependent growth of MERRF cybrids were rescued by WJMSCs-derived mitochondrial transfer 75
5.2.5 The rescue effect of mitochondrial transfer can last for upto 60 days 77
5.3 Summary 81
Chapter 6: Discussion 83
6.1 Project background 83
6.2 The creation of ρ0 cells and MERRF cybrids 83
6.3 Mitochondrial transfer from WJMSCs to ρ0 cells 84
6.4 Mitochondrial transfer from WJMSCs to MERRF cybrid 87
6.5 Conclusion 90
References 91
Appendix: Publications Arising from this Work 107

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