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系統識別號 U0026-1001201315454900
論文名稱(中文) 利用羊水幹細胞進行治療性血管新生
論文名稱(英文) Therapeutic Angiogenesis Using Amniotic Fluid-derived Stem Cells
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 101
學期 1
出版年 102
研究生(中文) 劉嚴文
研究生(英文) Yen-Wen Liu
學號 s98951136
學位類別 博士
語文別 英文
論文頁數 84頁
口試委員 指導教授-陳志鴻
指導教授-謝清河
口試委員-葉宏一
口試委員-林幸榮
口試委員-曾清俊
中文關鍵字 血管新生  缺血  幹細胞  羊水幹細胞  血管內皮細胞 
英文關鍵字 Angiogenesis  Ischemia  Stem cells  Amniotic fluid-derived stem cells  Endothelial cells 
學科別分類
中文摘要 在現代社會中,尤其是老年族群,動脈阻塞性疾病是項重要的健康問題。一般而言,動脈阻塞性疾病包括冠狀動脈疾病,週邊動脈阻塞性以及腦血管疾病。現今對於動脈阻塞性疾病的治療方式包含了藥物治療以及經由外科手術或是介入性導管治療的方式進行血管重建,但是病患的預後仍未達令人滿意的境地。以往的研究證實了「血管重建」對於治療動脈阻塞疾病病患的重要性。因此,對於病患的預後而言,如何改善缺血組織或是器官的血流灌注,便是相當的重要。

「血管新生」涉及了複雜的過程。然而,成熟的血管內皮細胞具有再生能力是有限的。在動物研究中,已經證實幹細胞可以用來誘導新生血管的形成。但是,並非所有的幹細胞治療都是有效的。人類胚胎幹細胞能分化成人體中各式各樣的細胞。然而,使用人類胚胎幹細胞的研究或治療一直受限於以下幾個問題:
(1) 複雜的社會觀感以及倫理爭議
(2) 免疫排斥反應
(3) 在受試者體內可能會生成腫瘤

以往的研究證實了羊水幹細胞正如同胚胎幹細胞,也具有高度的再生能力和分化能力。與胚胎幹細胞相比較,羊水幹細胞不會在動物體內誘發腫瘤新生,同時羊水幹細胞的研究並沒有嚴重的醫學倫理問題。因此,本研究的目的在於驗證,羊水幹細胞是否可以運用於治療動脈阻塞性疾病,並且誘發「血管再生」。在本研究中,我們證實了羊水幹細胞能在體外實驗中被誘導分化成血管內皮細胞。同時我們發現將老鼠的下肢動脈結紮造成下肢缺血,把分化的羊水幹細胞注射到缺血的肢體,發現小鼠經分化的羊水幹細胞治療後,有顯著的治療效果:大多數的缺血下肢得以保存,恢復血液灌注,患側肢體的微血管和小動脈密度有顯著增加。同時我們並未發現經分化的羊水幹細胞注射治療後,在小鼠體內發生急性排斥反應或生成腫瘤。最重要的是,移植分化的羊水幹細胞得以在缺血組織內的存活並且生成新生血管。

我們的研究證實「羊水幹細胞」是有潛力用於治療「動脈阻塞性疾病」。經由動物實驗,我們證明了分化的羊水幹細胞可以促進「血管新生」來治療動脈阻塞性疾病。相信在未來,經過捐贈者以及受贈者的細胞組織配對,羊水幹細胞可以運用於自體或是異體移植治療。
英文摘要 Artery occlusive diseases, including coronary artery disease, peripheral artery occlusive disease, and cerebrovascular disease, are major health issues that affect a large proportion of the adults, especially among aging population. Although there are several therapeutic strategies for artery occlusive diseases, i.e. optimal medical treatment and revascularization either by endovascular intervention or by open surgery, the prognosis is not satisfied. Therefore, how to improve blood perfusion in ischemic tissues should play a critical role in improving prognosis of patients with artery occlusive diseases. Previous studies highlighted the necessity of revascularization and reported that bone marrow-derived progenitor cells significantly enhanced cardiac repair by promoting neoangiogenesis. Consequently, to achieve efficient revascularization in ischemic regions is essential for restoring blood perfusion and physiologic function.

Angiogenesis is a tightly controlled process where endothelial cells proliferation and migration is regulated by secreted factors as well as by surrounding cells and matrix. However, mature endothelial cells possess limited regenerative capacity. Recently, mounting evidence showed that stem cells, such as endothelial progenitor cells, bone marrow stem cells, or cord blood stem cells, has been used to induce neovascularization in animal models of limb and myocardial ischemia, but unfortunately, the therapeutic efficacy of these stem cells is controversial. It is well-known that human embryonic stem cell (hESC) is pluripotent and can differentiate into a wide range of cell types representing the 3 primary embryonic lineages of mesoderm, ectoderm, and endoderm. However, the use of hESCs for research or therapeutic purposes has been constrained by several issues: complex social and ethical considerations, immune rejection reactions, and tumors formation in recipients.

Amniotic fluid-derived stem cells (AFSCs) are known to have a high renewal capacity and great differentiation potency. Unlike hESCs, the AFSCs do not form tumors in severe combined immunodeficient mice, and ASFC research does not raise profound ethical issues. Atala and his colleagues demonstrated that AFSCs are pluripotent and can be directed into a wide spectrum of cell types. Therefore, we conducted this study to test whether AFSCs can function as a cell source for therapeutic angiogenesis in a mouse hindlimb ischemia model: (1) to prove in vitro that AFS cells can be differentiated into endothelial lineage cell (EC), (2) to examine the in vivo therapeutic efficacy of AFSC or AFSC- derived EC (AFSC-EC) transplantation in a nude mice model of hindlimb ischemia, and (3) to identify the possible mechanisms of neoangiogenesis induced by AFSCs or AFSC-ECs.
We differentiated human AFSCs into ECs in vitro, as evidenced by expression of endothelial cell markers, and capillary-like network formation on Matrigel. One day after high ligation of the external iliac artery in athymic nude mice, AFSC-ECs were intramuscularly injected into ischemic limbs. As compared to AFSCs, HUVECs, and medium, intramuscular AFSC-EC injection into the ischemic regions improved limb salvage, restored blood perfusion, and significantly increased capillary and arteriole densities. We did not find any evidence of acute rejection or tumor formation in nude mice after intramuscular AFSC-EC injection, and most importantly, transplanted AFSC-ECs survived in the ischemic tissue. Those transplanted AFSC-ECs were incorporated into vessels in the ischemic region, as confirmed by immunofluorescent staining for human smooth muscle 22α or von Willebrand factor. Matrix metalloproteinase (MMP)-9 might stimulate VEGF-A release from AFSC-ECs and thus induce neovascularisation.

Our study indicates that AFSC-ECs were a suitable cell source for the treatment of artery occlusive diseases with therapeutic angiogenesis. AFSC-EC transplantation has the potential to promote therapeutic angiogenesis in vivo by facilitating neovascularization in a mouse model of ischemia. We conclude that AFSC-ECs can act as a novel source of xenograft, even allograft, transplantation cells for therapeutic angiogenesis in the treatment of ischemic diseases. In the future, AFSCs might be useful for autologous as well as nonautologous regenerative therapies via matching of histocompactible donor cells with recipients.
論文目次 CHINESE ABSTRACT I
ENGLISH ABSTRACT IV
ACKNOWLEDGEMENTS VIII
ABBREVIATIONS XI
CONTENT INDEX XIII
1. Introduction 1
1.1. Artery occlusive diseases 1
1.2. The need for understanding neovascularization in the ischemic region 1
1.3. Angiogenesis and vasculogenesis 2
1.4. Human embryonic stem cell is a useful cell type for regeneration. 3
1.5. Amniotic fluid-derived stem cell is another choice for regeneration. 4
1.6. Hypothesis 7
1.7. Specific aims and rationales 8
1.7.1. Specific Aim 1. To investigate the potential of endothelial differentiation of AFSCs in vitro. 8
1.7.2. Specific Aim 2. To test in vivo the therapeutic effect of angiogenesis using AFSCs and AFSC-ECs in the ischemic tissues. 8
1.7.3. Specific Aim 3. To explore the mechanisms how AFSC and AFSC-EC transplantation may improve angiogenesis/ vasculogenesis in ischemic tissue. 9
2. Materials and Methods 10
2.1. AFSC culture and endothelial differentiation 10
2.2. Characterization of AFSCs and AFSC-ECs 11
2.2.1. Reverse transcription-polymerase chain reaction (RT-PCR) 11
2.2.2. Flow cytometry analyses 12
2.2.3. Immunofluorescent staining 12
2.3. In-Vitro tube formation assays 14
2.4. Mouse limb ischemia and treatment 14
2.5. Laser Doppler blood flowmetry 15
2.6. Immuonofluorescent staining and evaluation 16
2.7. Enzyme-linked immunosorbent assay (ELISA) 17
2.8. Statistical analysis 17
3. Results 18
3.1. Phenotypic characterization of AFSCs 18
3.2. In vitro differentiation and characterization of AFSC-ECs 18
3.3. Improved limb salvage and blood perfusion in ischemic limbs after AFSC-EC transplantation 19
3.4. Increased neovascularization after AFSC-EC transplantation 21
3.5. Therapeutic effect of AFSC-EC supernatant injection 22
3.6. Role of transplanted AFSC-ECs in neovascularization of the ischemic limbs 23
3.7. Roles of MMP-3 and MMP-9 in neovascularization of AFSC-ECs 23
4. Discussion 25
4.1. Advantages of AFSCs and AFSC-ECs application in cell therapy 25
4.2. Neovascularisation induced by AFSC-ECs transplantation 26
4.3. Effects of single intramuscular AFSC-EC supernatant injection 29
4.4. Possible molecular mechanisms of MMP-3 and -9 in the neovascularisation of AFSC-ECs 30
4.5. Immunogenicity and in vivo tumor formation of AFSC and AFSC-EC transplantation 31
4.6. Study limitations 32
5. Perspective 33
6. Conclusions 35
7. References 36
8. Tables Contents 56
Table 1. The list of human specific primers 57
Table 2. Statistical anaylsis results of “Test of Homogeneity of Variances” 58
9. Figure Contents 59
Figure 1. Experimental design 63
Figure 2. Phenotypic characteristics of AFSCs. 64
Figure 3. Characterization of AFSC-ECs. 65
Figure 4. Transplantation of AFSC-ECs improved limb salvage after hindlimb ischemia. 69
Figure 5. Transplantation of AFSC-ECs enhances neovascularization after hindlimb ischemia. 71
Figure 6. Injection of AFSC-EC supernatant into ischemic hindlimbs neither improved blood flow nor enhanced neovascularization. 74
Figure 7. Engraftment of transplanted AFSC-ECs into vascular structures of the ischemic limbs. 76
Figure 8. Roles of MMP-3 and 9 in AFSC-ECs. 77
APPENDIX 79
AWARDS AND HONORS 80
RECENT PUBLICATIONS 81
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