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研究生:陳永斌
研究生(外文):Young-Bin Chen
論文名稱:開發白藜蘆醇透過誘導HSP70啟動子大量表現血管内皮生長因子之新穎幹細胞與基因療法系統
論文名稱(外文):Developing a novel stem cell and gene therapy system based on resveratrol-induced HSP70 promoter-regulated VEGFA expression
指導教授:李宣書李宣書引用關係
口試委員:鄭 登 貴吳 信 志陳 全 木
口試日期:2015-07-27
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:135
中文關鍵詞:幹細胞與基因治療白藜蘆醇HSP70啓動子血管內皮生長因子A血管新生肺氣腫動物模式
外文關鍵詞:Stem cell-based gene therapyResveratrolHSP70 promoterVEGFAangiogenesisemphysemamouse model
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中文摘要
研究指出利用血管內皮生長因子(VEGFA)基因療法或間質幹細胞(MSC)移植,成功讓肢體缺血和心臟衰竭等減少(因缺血而損傷),且具持續再生的效果。基因改良的MSCs增強改善血管缺血性損傷。此外,研究也證明MSC透過分泌抗凋亡因子和抗炎因子等旁分泌因子來改善大鼠肺氣腫及降低肺損傷。儘管如此,但移植之MSC容易受到損傷微環境之傷害而死亡,而造成應用MSC治療的障礙,開發新穎幹細胞與基因療法系統成為當務之急。為避免VEGFA過度表現所造成多項副作用,我們建立調控式大量表現VEGFA (以HSP70的啟動子調控;只有在白藜蘆醇刺激時才大量表現)之幹細胞與基因治療系統,並以血管新生動物模式及肺氣腫動物模式來評估其療效。第一部份,白藜蘆醇處理HSP70-VEGFA-MSC細胞時有效調控HSP70啟動子表現VEGFA增加2倍,其培養液具誘發人類臍帶靜脈內皮細胞 (HUVEC) 管狀形成的能力。白藜蘆醇長期處理HSP70-VEGFA-MSC,該細胞呈現血管內皮細胞特殊形態及表現內皮細胞特異細胞標記。在體外小鼠主動脈環發芽分析中發現其促進動脈組織新生出小血管及細胞。再者,在體內移植也顯示基因改良的MSCs移植區域,血管明顯比較密集及血管管徑明顯較粗壯等促進血管生成的能力。第二部份,當利用香煙萃取物刺激白藜蘆醇處理HSP70-VEGFA-MSC細胞時,可協同HSP70轉錄活性、誘導Nrf2及HO-1等抗氧化基因表現。再者,以頸靜脈注射HSP70-VEGFA-MSC於elastase誘導肺氣腫的小鼠模式,餵食白藜蘆醇的八週後實驗組中發現肺部功能有明顯改善、肺部VEGFA, Nrf2及HO-1等基因表現皆有明顯上升。在肺部組織切片中肺氣腫的損傷有明顯的下降及肺泡組織結構有明顯恢復。綜合所述,本論文驗證了HSP70-VEGFA-MSC幹細胞與基因治療系統中,白藜蘆醇調控HSP70啓動子誘導表現VEGFA,有效促進血管新生成作用及修復肺氣腫損傷,且可避免過量表現VEGFA所造成的副作用。


ABSTRACT
Several studies of stem cell-based gene therapy have indicated that long-lasting regeneration following vessel ischemia may be stimulated through VEGFA gene therapy and/or mesenchymal stem cell (MSC) transplantation for reduction of ischemic injury in limb ischemia and heart failure. The therapeutic potential of MSC transplantation can be further improved by genetically modifying MSCs with genes which enhance angiogenesis following ischemic injury. Furthermore, several studies have demonstrated that MSC-based cell therapy results in improvement in the treatment of emphysema in rat models. MSCs secrete anti-apoptotic and anti-inflammatory paracrine factors and reduce lung injuries. Despite reported successes, it was demonstrated that the amount of engrafted MSCs decreased dramatically after 24 hours of transplantation due to exposure to toxic and oxidative microenvironments. In additions, several possible side effects that may arise from clinical applications of VEGFA should be closely monitored. To avoid the VEGFA complications, we propose to further examine the protective effect of a conditional overexpression of VEGFA (under Resveratrol induced HSP70 promoter regulation) in two animal models. In this work, we aimed to test that VEGFA expression increased by RSV acting on the HSP70 promoter in transplanted MSC augments the angiogenic effects in a mouse angiogenesis model and protects against elastase-induced pulmonary emphysema in a mouse model by using stem cell and gene therapy. In the first study, HSP70 promoter-driven VEGFA expression was induced by resveratrol (RSV) in MSCs, and in combination with known RSV biological functions, to develop MSC-based therapy for repair and mitigation of ischemic injury and regeneration of damaged tissues in ischemic disease. We investigated the protective effects of our approach by using ex vivo aortic ring co-culture system and 3D scaffolds in vivo model. Results of first investigation demonstrated that HSP70 promoter-driven VEGFA expression in MSC increased approximately 2-fold over the background VEGFA levels upon HSP70 promoter induction by RSV. Exposure of HUVEC cells to medium containing MSC in which VEGFA had been induced by c-RSV enhanced tube formation in the treated HUVEC cells. RSV-treated MSC cells differentiated into endothelial-like phenotypes, exhibiting markedly elevated expression of endothelial cell markers. These MSCs also induced aortic ring sprouting, characteristic of neovascular formation from pre-existing vessels, and additionally promoted neovascularization at the MSC transplantation site in a mouse model. In the second study, this same stem cell line was further evaluated for its protective capacity to alleviate elastase-induced pulmonary emphysema in mice. Results of second study showed that c-RSV-treatment of HSP-VEGFA-MSC exhibited synergy between HSP70 transcription activity and induced expression of antioxidant-related genes when challenged by cigarette smoke extracts. Eight weeks after jugular-vein injection of HSP-VEGFA-MSC into mice with elastase-induced pulmonary emphysema, followed by c-RSV treatment to induce transgene expression, significant improvement was observed in respiratory functions. Expression of VEGFA, endogenous Nrf2 and MnSOD was significantly increased in the lung tissues of the c-RSV-treated mice. Histopathologic examination of treated mice revealed gradual but significant abatement of emphysema and restoration of airspace volume. In conclusion, the present investigation demonstrates that resveratrol-regulated VEGFA expression in HSP-VEGFA-MSC significantly improved the therapeutic effects on the treatment of ischemic disease and COPD in the mouse, possibly avoiding side effects associated with constitutive VEGFA expression.



CONTENTS

致謝 I
中文摘要 II
ABSTRACT IV
CONTENTS VII
LIST OF FIGURES XII
LIST OF TABLE XIV
ABBREVIATIONS XV
CHAPTER 1 LITERATURE REVIEW 1
1.1. Vascular endothelial growth factor A (VEGFA) 2
1.2. Role and characteristics of VEGFA in chronic obstructive pulmonary disease (COPD) 4
1.3. Role and characteristics of VEGFA in ischemic vascular disease 6
1.4. Oxidant and inflammation 8
1.5. Tobacco smoke pollution and air pollution-induced cellular oxidative stress 10

1.6. Nuclear factor erythroid 2-related factor 2 (Nrf2) 12
1.7. Resveratrol and cellular stress 14
1.8. HSP70 in COPD 17
1.9. Mesenchymal stem cells for treatment of lung injury 18
1.10. Promoter systems in gene therapy 21
1.11. Inducible promoters 22
CHAPTER 2 AIMS OF STUDY 25
CHAPTER 3 MESENCHYMAL STEM CELL-BASED HSP70 PROMOTER-DRIVEN VEGFA INDUCTION BY RESVERATROL PROMOTES ANGIOGENESIS IN A MOUSE MODEL 29
3.1. Introduction 30
3.2. Materials and methods 32
3.2.1. Cell lines 32
3.2.2. Preparation of conditioned medium 33
3.2.3. Construction of lentiviral vectors and transduction into MSCs 33
3.2.4. Cell proliferation test 35
3.2.5. Cell viability MTT assay 35
3.2.6. Luciferase activity assay 35
3.2.7. Quantitative real-time RT-PCR 36
3.2.8. Western blot analysis 36
3.2.9. Heat shock challenges 38
3.2.10. Tube formation ability assay 38
3.2.11. Aortic ring coculture MSCs 38
3.2.12. Formation of 3D scaffolds in vivo 39
3.2.13. Endothelial induction of MSCs 40
3.2.14. Statistical analysis 40
3.3. Results 41
3.3.1. Low-dosage RSV treatment does not cause acute cytotoxicity in MSCs and HUVECs 41
3.3.2. HSP70 promoter-driven transgene expression is effectively activated by RSV and/or heat shock in HSP-VEGFA-MSC stable cell 41
3.3.3. RSV induces endothelial differentiation in MSCs and promotes tube formation in HUVECs 42
3.3.4. RSV conditionally regulates HSP-VEGFA-MSC-dependent angiogenesis in aortic rings ex vivo and in 3D scaffolds in vivo 44
3.4. Discussion 45
CHAPTER 4 MESENCHYMAL STEM CELL-BASED HSP70 PROMOTER-DRIVEN VEGFA INDUCTION BY RESVERATROL ALLEVIATES ELASTASE-INDUCED EMPHYSEMA IN A MOUSE MODEL 50
4.1. Introduction 51
4.2. Materials and methods 55
4.2.1. Cell culture 55
4.2.2. Preparation of cigarette smoke extract 55
4.2.3. MTT cell viability assay 55
4.2.4. Luciferase activity assay 56
4.2.5. Quantitative real-time RT-PCR 56
4.2.6. Western blot analysis 57
4.2.7. Construction of lentiviral vector and transduction into MSCs 58
4.2.8. Porcine pancreatic elastase-induced emphysema mouse model 59
4.2.9. Noninvasive measurement of pulmonary functions by whole-body plethysmography (WBP) 60
4.2.10. Morphometric assessment 61
4.2.11. Immunohistochemical staining for beta-galactosidase protein 61
4.2.12. Statistical analysis 62
4.3. Results 63
4.3.1. Induction of transcription activities of HSP and ARE and enhanced cell survival in RSV-treated MSCs after CSE challenge 63
4.3.2. Induction of Nrf2 and HO-1 in response to c-RSV treatment 64
4.3.3. Improvement of pulmonary respiratory functions in the lungs of PPE-induced emphysema on c-RSV co-treatment of HSP-VEGFA-MSC transplant 65
4.3.4. Upregulated expression of antioxidant-related genes and VEGFA in c-RSV co-treatment of HSP-VEGFA-MSC transplantation in the lungs of PPE-induced emphysema 65
4.3.5. c-RSV co-treatment of HSP-VEGFA-MSC transplantation alleviates histological changes in the lungs of PPE-emphysema 66
4.4. Discussion 69
CONCLUSION 73
FIGURE AND LEGENDS 74
TABLE………... 99
REFERENCES 100
CURRICULUM VITAE 112
APPENDIX… 114




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