臺灣博碩士論文加值系統

2006年日本學者Shinya Yamanaka外送四個基因Oct3/4, Sox2, Klf4, c-Myc可以將成熟的體細胞成功地再細胞重組為具有多功能的幹細胞 （Induced pluripotent Stem Cells, iPSCs）。這種方法不需要從胚胎中取得幹細胞，因此解決了舊技術在道德上的爭議，另一個優點是纖維母細胞可從患者的皮膚直接取得，所以製造出來的分化細胞便不會有免疫排斥問題，可作為病理研究及藥物篩選平台。

目前研究顯示，活性氧化物質可激活信號傳導、轉錄因子等各式各樣方式表現，導致細胞生長、基質重塑及心肌細胞功能缺損。近年來發現，體外培養心肌細胞，會受血管壓力素、內皮素、腎上腺素、腫瘤壞死因子α（TNF-α）及心搏動機械拉伸的刺激，促使細胞內產生活性氧化物質和抗氧化劑。

綜合我們的研究發現，過氧化氫對iPSCs細胞的生存能力有一個雙向作用。在3.125-25 uM濃度範圍內沒有細胞毒性。低濃度6.25 uM的過氧化氫會刺激iPSCs細胞增殖（平均增加12.5％）（P <0.05）。若暴露於高濃度 (>50 uM) 過氧化氫時，促使iPSCs死亡，具顯著毒性（P <0.001）。最後我們發現相較於基礎值，低濃度6.25 uM的過氧化氫會刺激iPSCs細胞產生IL-6、IL-1β及TGF-β1（P <0.01）。

In 2006, Shinya Yamanaka discovered four genes Oct3/4, Sox2, Klf4, c-Myc that can successfully reprogram somatic cells into a pluripotent stem cells (Induced pluripotent Stem Cells, iPSCs). Employment of iPSCs as in vitro experiment platform does not need to isolate stem cells from the embryo and therefore can be carried out without the conventional ethical issues. Another advantage of such platform is that the somatic cells for cell reprogramming can be obtained directly from the patients’ skin and prevent the possibility of immune rejection. It has been reported that ROS stimulates cell growth, matrix remodeling, and cellular dysfunction in cardiomyocytes through activation of a broad variety of hypertrophic and apoptotic signaling pathways and transcription factors. In addition, intracellular ROS production and antioxidants can be elicited by various exogenous stimuli in vitro. The data revealed that there was a biphasic effect of H2O2 on the viability of iPSCs. Cytotoxicity was not observed in the concentration range of 3.125–25 μM H2O2 when the iPSCs were incubated with H2O2 for 24h. In contrast, lower concentrations of H2O2 increased the survival of iPSCs with the peak proliferation (mean increase: 12.5%) at 6.25 μM H2O2 (p<0.05). When the iPSCs were exposed to H2O2 at a concentration of 50 μM or above, significant cytotoxicity was observed (p<0.001). Basal levels of TGF-β1 and IL-1β were significantly higher in the iPSCs compared with those of the control group (p<0.01 and p<0.01, respectively). Low concentrations of H2O2 led to significant elevation IL-6, IL-1β and TGF-β1 levels in iPSCs compared with the respective controls (p<0.01).

CONTENTS

Contents i
Chinese Abstract iv
English Abstract vi
List of abbreviations viii
Chapter 1 Introduction 1
1.1 Induced pluripotent stem cells (iPSCs) 2
1.2 Fabry disease 4
1.3 Proinflammatory cytokines 5
1.4 Reactive oxidative stress 6
1.5 Enzyme replacement therapy 7
1.6 Experimental design 8
Chapter 2 Materials and Methods 9
2.1 Human iPSC generation and cultivation 10
2.2 iPSCs-derived cardiomyocytes 11
2.3 Alkaline Phosphatase (AP) staining 12
2.4 Reverse Transcription-Polymerase Chain Reaction (RT-PCR) 13
2.5 Genomic DNA extraction 14
2.6 Immunofluorescence staining 15
2.7 GLA enzyme activity 16
2.8 Cell thawing 17
2.9 Quantitative RT-PCR 18
2.10 Measurements using ELISA 19
2.11 Liquid chromatography for lyso-Gb3 and Gb3 analysis 20
2.12 MTT assay 21
2.13 Measurement of reactive oxygen species content 22
2.14 Statistical analyses 23
Chapter 3 Results 24
3.1 Establishment of iPSC-derived cardiomyocytes from FD patients carrying GLA IVS4+919 G>A mutation 25
3.2 Effects of various concentrations of hydrogen peroxide on the viability of Fabry-iPSCs. 28
3.3 Low concentration of hydrogen peroxide–induced changes of
intracellular cytokines in Fabry-iPSCs. 29
3.4 Modulation of low concentration hydrogen peroxide–induced cellular
proliferation and changes of intracellular levels of transforming
growth factor, beta 1 and interleukin-1β in Fabry-iPSCs with various
antioxidants 30
3.5 Low concentration of hydrogen peroxide–induced changes of
reactive oxygen species in Fabry-iPSCs. 31
3.6 Lysosomal abnormalities and upregulation of proinflammatory cytokines in patients with FC 32
3.7 Use of echocardiography, lyso-Gb3, and pro-inflammatory cytokines for monitoring ERT efficacy in patients with FC 33
3.8 Patients with Fabry cardiomyopathy exhibited left ventricular hypertrophy, glycosphingolipid deposition, and increased oxidative stress 34
3.9 Enzyme Replacement Therapy decreased left ventricular mass and serum lysoGb3 levels, and ameliorated oxidative stress in Patients with Fabry Cardiomyopathy 35
3.10 The 8OHdG is a sensitive biomarker in the FC patients with poor response to ERT 36
Chapter 4 Discussion 37
Chapter 5 Conclusion 41
Chapter 6 Perspectives 43
Chapter 7 References 45
Chapter 8 Figures and Table 56
Chapter 9 Publications 86

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