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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳彥榮 | zh_TW |
| dc.contributor.advisor | Edward Chern | en |
| dc.contributor.author | 石政弘 | zh_TW |
| dc.contributor.author | Jheng-Hong Shih | en |
| dc.date.accessioned | 2025-07-11T16:12:06Z | - |
| dc.date.available | 2025-07-12 | - |
| dc.date.copyright | 2025-07-11 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-07-03 | - |
| dc.identifier.citation | 1. Friedenstein, A.J., et al., Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation, 1968. 6(2): p. 230-47.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97690 | - |
| dc.description.abstract | 間質幹細胞（Mesenchymal stem cells, MSCs）是維持體內器官穩定性的重要細胞群。然而，隨著年齡的增長，體內 MSCs 的活性和數量逐漸下降，這不僅影響健康，還限制了細胞療法的應用。雖然亞精胺（Spermidine, Spd）等多胺被認為有助於器官保護和延長生物體壽命，但它們對 MSCs 的影響仍不明確。本研究顯示，Spd 透過活化 AMPK 來促進自噬作用，並調節 MSCs 的增殖、遷移和分化。在氧化壓力下，Spd 能減少 MSCs 中的活性氧和炎症。In Vivo 結果顯示，給予 Spd 可以提升小鼠體內 MSCs 的活性，並開啟自噬作用改善老化。為了解決 MSCs 的來源問題，本研究透過化學再程序化(Chemical reprogramming)獲得了人類化學誘導多能幹細胞（hCiPSCs），並將其分化為類似於人類臍帶間質幹細胞（hUC-MSCs）和脂肪來源的間質幹細胞（hADSCs）的人類誘導間質幹細胞(hiMSCs)，這些細胞具有更好的增生和穩定性。組織工程是再生醫學的重要組成部分，利用支架和特定細胞組裝功能性仿生結構。本研究透過胰蛋白酶去細胞化得到豬主動脈的細胞外基質（ECM），以促進生物廢棄物的再利用。此外，本研究成功將 hiMSCs 移植至豬主動脈 ECM 中，使其分化為成熟的軟骨層，並展現出良好的生物相容性。綜上所述，Spd 對於提升 MSCs 的活性有顯著益處，為健康老化提供了新的保健選擇。此外，本研究確立了豬主動脈 ECM 的可用性，並與個人化 hiMSCs 流程相結合，為未來的組織工程提供了全新的方案。 | zh_TW |
| dc.description.abstract | Mesenchymal stem cells (MSCs) are regarded as a crucial cell population for maintaining organ homeostasis. However, with aging, the activity and quantity of MSCs are progressively reduced, impacting overall health and limiting cell therapy application. Although polyamines such as spermidine (Spd) have been suggested to contribute to organ protection and lifespan extension, their effects on MSCs remain unclear. This study demonstrated that Spd promotes autophagy through AMPK activation and regulates the proliferation, migration, and differentiation of MSCs. Under oxidative stress, Spd was shown to reduce reactive oxygen species (ROS) and inflammation in MSCs. In Vivo results showed that administration of Spd could enhance the activity of MSCs in mice and activate autophagy to improve aging. To address the issue of MSC sourcing, human chemically induced pluripotent stem cells (hCiPSCs) were obtained through chemical reprogramming and subsequently differentiated into human-induced MSCs (hiMSCs) resembling human umbilical cord MSCs (hUC-MSCs) and adipose-derived MSCs (hADSCs). These hiMSCs exhibited superior proliferation and stability. Tissue engineering, a critical component of regenerative medicine, involves assembling functional biomimetic structures using scaffolds and specific cells. In this study, extracellular matrix (ECM) from porcine aorta was obtained through trypsin-based decellularization, facilitating the reutilization of biological waste. Furthermore, hiMSCs were successfully implanted into the porcine aorta ECM, where they differentiated into mature cartilage layers and demonstrated excellent biocompatibility. In conclusion, Spd was shown to significantly enhance MSC activity, offering a novel option for promoting healthy aging. Additionally, the usability of porcine aorta ECM was established, and its integration with the personalized hiMSCs process provides an innovative approach for future tissue engineering. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-07-11T16:12:06Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-07-11T16:12:06Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 誌謝 II
摘要 III Abstract IV List of Abbreviations VI Table of Content VII Chapter 1: Mesenchymal Stem Cells: Applications and Challenges 1 Introduction 1 1.1 Mesenchymal Stem Cells (MSCs) 1 1.1.1 The Origin of MSCs 1 1.1.2 The Definition Criteria for MSCs 2 1.1.3 Functional Properties and Clinical Applications of MSCs 2 1.1.4 Functional Decline and Aging of MSCs 5 1.1.5 Functional Inactivation of MSCs and Strategies to Restore Their Potency 6 1.1.6 The Dilemma of MSCs Sources 8 1.2 Pluripotent Stem Cells (PSCs) 9 1.2.1 The Advent of Induced Pluripotent Stem Cells (iPSCs) 9 1.2.2 Chemical Reprogramming 10 1.2.3 Establishing iMSCs Using iPSCs 12 1.2.4 Current Applications of iPSC-Derived MSCs (iMSCs) 13 Motivation and Aim 15 Chapter 2. Spermidine Regulated Mesenchymal Stem Cell Status and Ameliorate Age-related Decline by Activating AMPK and Autophagy 17 Introduction 17 2.1 Spermidine (Spd) 17 2.1.1 Overview 17 2.1.2 Biosynthesis and Metabolism of Spd 17 2.1.3 Source of Spd in the Human Body 19 2.1.4 Spd and Lifespan Extension 19 2.1.5 The Primary Molecular Mechanism of Spd 21 2.1.6 Spd and Mitochondrial Metabolism in Aging 25 2.1.7 Cellular Uptake of Spd and Autophagy Activation 27 Motivation and Aim 28 Materials and Methods 30 2.1 Human Adipose Mesenchymal Stem Cells (hADSCs) Isolation 30 2.2 Mouse Bone Marrow Mesenchymal Stem Cells (mBM-MSCs) Isolation 31 2.3 Self-isolated hADSCs and mBM-MSCs Culture 33 2.4 Cell Viability Assay 35 2.5 Flow Cytometry 36 2.6 Protein Extraction and Western Blot 38 2.7 Real-time Polymerase Chain Reaction (qPCR) 40 2.8 Cell Cycle Analysis 41 2.9 BrdU Incorporation Assay 42 2.10 Wound Healing Assay 43 2.11 Cell Migration Assay 44 2.12 Osteogenesis Differentiation and Alizarin Red S Staining 45 2.13 Adipogenesis Differentiation and Oil Red O Staining 47 2.14 Chondrogenesis Differentiation and Alcian Blue Staining 48 2.15 Hydrogen Peroxide (H2O2) Aging Induction 49 2.16 Senescence-associated β-galactosidase (SA-β-gal) Staining 50 2.17 Reactive Oxygen Species (ROS) Analysis 51 2.18 Mitochondrial ROS Analysis 52 2.19 Mitochondrial Membrane Potential Analysis 52 2.20 In vivo Spd Treatment Assay 53 2.21 Colony Forming Unit-Fibroblastic (CFU-F) Assay 54 2.22 Statistical Analysis 55 Experimental Strategy 56 Results 57 2.1 Successful Isolation of MSCs (hADSCs) from Human Adipose Tissue 57 2.2 Spd Promoted Autophagy in hADSCs through AMPK Phosphorylation 57 2.3 Spd Inhibited Cell Proliferation of hADSCs and Promoted Cell Migration 58 2.4 Spd Promoted Osteogenesis and Chondrogenesis of hADSCs While Inhibiting Adipogenesis 59 2.5 Spd Reduced H₂O₂-Induced Oxidative Stress in hADSCs 60 2.6 Spd Increased Cell Viability and Mitigated Senescence with Pretreatment 62 2.7 Spd Increased the Cell Viability of Bone Marrow MSCs In Vivo and Maintained Organ Status through the AMPK Autophagy Pathway 63 2.8 Crucial Role of AMPK Phosphorylation in Spd-Mediated Protection against Oxidative Stress 64 Summary of Chapter 2 65 Discussion 66 2.1 AMPK Is Essential for Various Functions of MSCs 66 2.2 Spd May Benefit More Than Just MSCs Themselves 70 2.3 Spd May Induce a Quiescent State in MSCs 73 2.4 Dietary Supplementation of Spermidine: Debates and Insights 74 2.5 Dual Effects of Spd in Cancer 76 Figures and Tables 79 Figure 1 79 Figure 2 81 Figure 3 85 Figure 4 87 Figure 5 89 Figure 6 93 Figure 7 97 Figure 8 101 Figure 9 105 Figure 10 108 List of Antibodies 111 List of qPCR Primers 112 Chapter 3. Decellularized Porcine Aorta as a Scaffold for Personalized Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells in Tissue Engineering 117 Introduction 117 3.1 The Human Trachea 117 3.1.1 Overview 117 3.1.2 Clinical Disorders 117 3.1.3 Surgical Challenges 119 3.2 Tissue Engineering Scaffold 120 3.2.1 Clinical Artificial Stents 120 3.2.2 Animal-Derived Scaffolds 121 3.2.3 Tissue Decellularization 122 3.3 Tubular Tissue Scaffold 123 3.3.1 Aortic Stents 123 3.3.2 Scaffold Recellularization 124 Motivation and Aim 126 Materials and Methods 128 3.1 Generate Human Pluripotent Stem Cells by Chemical Reprogramming (hCiPSCs) 128 3.2 Human Induced Pluripotent Stem Cells (hiPSCs) Culture 132 3.3 Differentiation of Human Induced Mesenchymal Stem Cells (hiMSCs) 133 3.4 Differentiation of Human Induced Dental Pulp Mesenchymal Stem Cells (hiDPMCs) 134 3.5 Differentiation of Human Platelet Lysate Induced Mesenchymal Stem Cells (hPL-iMSCs) 135 3.6 Cell Doubling Time 136 3.7 Immunofluorescence Staining (IF) 137 3.8 RNA-Seq Data Processing and Analysis 138 3.9 Co-Culture of Mouse Splenocytes 139 3.10 Porcine Aorta Decellularization Procedure 140 3.11 DNA Residue Analysis 141 3.12 Compliance Force 141 3.13 Recellularization of Decellularized Aorta 142 3.14 Decellularized Aortic Component Migration Assay 142 3.15 Biocompatibility Test 143 Experimental Strategy 144 Results 146 3.1 Chemical Reprogramming of hADSCs into hCiPSCs 146 3.2 Differentiation of hCiPSCs into hiMSCs with MSC Marker Expression and Differentiation Potential 146 3.3 hiMSCs Exhibit Enhanced Proliferation and Maintenance Capabilities Compared to hADSCs 148 3.4 Distinct Strengths in the Capabilities of Different iMSCs 150 3.5 Successful Removal of Porcine Aortic Cells by Trypsin 152 3.6 Both hiMSCs and hADSCs Maintained Viability and Differentiated into Chondrocytes on Decellularized Aortas 154 3.7 Decellularized Aortas Retained Components that Facilitate Migration of hiMSCs and hADSCs 155 3.8 Optimal Biocompatibility of Aortic Recellularization with MSCs 156 Summary of Chapter 3 158 Discussion 160 3.1 Advantages and Process Analysis of Chemical Reprogramming 160 3.2 Changes in Epigenetics May be Key to Achieving Rejuvenation 161 3.3 hiMSCs May Have Greater Advantages in Tissue Regeneration Medicine 163 3.4 Comparison of iMSC and Primary MSC in Exosomes (EVs) 164 3.5 Establishment of Personalized Cells to Meet Specific Needs 166 3.6 The Establishment of Cancer-iPSCs Provides New Insights into Cancer Treatment 169 3.7 Trypsin as an Effective Method for Obtaining Aortic ECM 172 3.8 MSC Differentiation and Immunomodulatory Abilities Favor Tissue Regeneration Applications 173 Figures and Tables 176 Figure 11 176 Figure 12 179 Figure 13 182 Figure 14 186 Figure 15 190 Figure 16 195 Figure 17 198 Figure 18 201 Figure 19 204 Figure 20 207 List of Chemicals 211 Tranylcypromine hemisulfate 211 Forskilin 211 Bafilomycin A1 211 SB431542 211 List of Antibodies 212 List of qPCR Primers 213 Chapter 4: Conclusion and Outlooks 217 Conclusion 217 Outlook 219 Summary 221 Reference 222 | - |
| dc.language.iso | en | - |
| dc.subject | 亞精胺 | zh_TW |
| dc.subject | 自噬作用 | zh_TW |
| dc.subject | 人類誘導多能幹細胞 | zh_TW |
| dc.subject | 豬主動脈 | zh_TW |
| dc.subject | 細胞外間質 | zh_TW |
| dc.subject | 軟骨細胞 | zh_TW |
| dc.subject | 間質幹細胞 | zh_TW |
| dc.subject | Chondrocytes | en |
| dc.subject | Mesenchymal stem cells | en |
| dc.subject | Spermidine | en |
| dc.subject | Autophagy | en |
| dc.subject | Human induced pluripotent stem cells | en |
| dc.subject | Porcine aorta | en |
| dc.subject | Extracellular matrix | en |
| dc.title | 從細胞活性改善到組織再生：間質幹細胞在個人化應用之研究探索 | zh_TW |
| dc.title | From Cellular Activity Enhancement to Tissue Regeneration: Advances in Mesenchymal Stem Cell Personalized Applications | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 李昆達;黃楓婷;侯詠德;黎萬君 | zh_TW |
| dc.contributor.oralexamcommittee | Kung-Ta Lee;Feng-Ting Huang;Yung-Te Hou;Wan-Chun Li | en |
| dc.subject.keyword | 間質幹細胞,亞精胺,自噬作用,人類誘導多能幹細胞,豬主動脈,細胞外間質,軟骨細胞, | zh_TW |
| dc.subject.keyword | Mesenchymal stem cells,Spermidine,Autophagy,Human induced pluripotent stem cells,Porcine aorta,Extracellular matrix,Chondrocytes, | en |
| dc.relation.page | 242 | - |
| dc.identifier.doi | 10.6342/NTU202501436 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-07-04 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| dc.date.embargo-lift | 2030-06-30 | - |
| 顯示於系所單位： | 生化科技學系 | |
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