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系統識別號 U0026-1501201416004700
論文名稱(中文) 自體骨髓單核球細胞結合玻尿酸水膠於心血管疾病的前臨床研究
論文名稱(英文) Preclinical studies of cardiovascular repair using autologous bone marrow mononuclear cells and hyaluronan hydrogel
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 102
學期 1
出版年 103
研究生(中文) 陳建熹
研究生(英文) Chien-Hsi Chen
學號 S98981018
學位類別 博士
語文別 英文
論文頁數 99頁
口試委員 指導教授-謝清河
口試委員-黃效民
口試委員-王水深
口試委員-林睿哲
口試委員-莫凡毅
中文關鍵字 細胞治療  心肌梗塞  玻尿酸水膠 
英文關鍵字 cell therapy  myocardial infarction  hyaluronan hydrogel 
學科別分類
中文摘要 摘要
冠狀動脈疾病(CAD)是最常見的心臟疾病。CAD通常是由於動脈粥狀硬化使冠狀動脈變狹窄所導致。在此條件之下,供給心肌細胞的血流量會減少進而導致心肌缺血,甚至造成心肌梗塞。遺憾的是目前的標準療程,並不足以修復受損的心臟。之前的研究發現,細胞治療對於心臟的修復是一種具有前景的療法。此外,一些臨床試驗也證明了自體細胞療法,如骨髓單核球細胞可以在心肌梗塞後促進心臟的功能。然而有些臨床試驗卻得到相反的結果。最主要造成治療結果有爭議的原因在於,只有一小部分的細胞可以在移植後存活並保留在缺氧的環境之下。因此,一種生物相容的水膠-玻尿酸,已被證明可以增加血管新生、促進傷口癒合並減少疤痕組織產生,且在心臟血管發育扮演重要的角色,被認為可當作細胞的載體,來傳遞並使骨髓單核球細胞保留在梗塞的心肌。在第一個研究當中,我們假設玻尿酸水膠結合骨髓單核球細胞,在小動物-大鼠心肌梗塞模式中,是否可以增進心臟的功能。為了更進一步證明此療法對於臨床的應用是否有幫助,第二部分的研究利用大型動物-蘭嶼迷你豬來測試此療法,對於心肌梗塞是否有治療效果。最後我們證明了此療法,可透過減少疤痕組織的生成、膠原蛋白的累積、及吸引內生性的細胞到受損的位置,參與血管新生。因此我們認為此玻尿酸結合骨髓單核球細胞療法,在未來有機會應用在臨床治療上。
英文摘要 Abstract
Coronary artery disease (CAD) is the most common type of heart disease. CAD occurs when the coronary arteries narrow as a result of atherosclerosis. Atherosclerosis decreases the blood flow that supplies the heart muscle and can lead to myocardial ischemia or even infarction (MI). Unfortunately, the current standard treatments are not sufficient to repair the injured heart in these cases and heart failure is the eventual outcome. Previous studies have shown that cell therapy is a promising approach for heart repair. Some clinical trials have also demonstrated that autologous cell therapy such as bone marrow mononuclear cells (BMMNCs) can improve cardiac function after MI. However, the results of these clinical studies remain controversial. The major reason for the controversy is that only a small portion of cells survive and are retained in the ischemic region after cell transplantation. A biocompatible hyaluronan (HA) hydrogel which has been proved to increase angiogenesis, enhance scarless wound healing, and also play an important role during heart vasculature development has been considered as a carrier to deliver BMMNCs into the infarcted heart. In our first study, we hypothesized that injection of HA hydrogel combined with BMMNCs may improve cardiac performance post-MI in a small animal MI model. To translate the combined treatment approach into clinical applications, our second study used a large animal model (mini pigs) to test the therapeutic benefits post-MI. We showed that the combined treatment improves cardiac performance by reducing scar size and collagen accumulation in the remote area, and by recruiting endogenous cells to the injury site for new blood vessel formation. Therefore, we postulate that HA/MNC therapy can be translated into a clinical treatment for MI.
論文目次 Index of Contents
Abstract I
摘要 III
誌謝 IV
Abbreviations V
Index of Figures VIII
Index of table X
Chapter 1 Introduction 1
1.1 Cardiovascular disease remains leading cause of death worldwide 1
1.2.2 Pharmacological approaches for cardioprotection 3
1.2.3 Cell therapy is a promising approach for ischemia heart disease 4
1.2.4 Tissue engineering to improve the therapeutic efficacy of cell therapy 5
Chapter 2 Hyaluronan Enhances Bone Marrow Cell Therapy for Myocardial Repair After Infarction 8
2.1 Background 8
2.2 Materials and Methods 10
2.2.1 Preparation of the coated plates 10
2.2.2 Experimental animals 11
2.2.3 Bone marrow MNC isolation, purification, and receptor analysis 11
2.2.4 Bone marrow MNC apoptosis analysis 12
2.2.5 Bone marrow MNC adhesion, proliferation, differentiation and gene Expression 12
2.2.6 MI model and treatment 15
2.2.7 Echocardiograph 15
2.2.8 DiI labeling of MNCs 16
2.2.9 Immunofluorescence and Masson’s trichrome staining 16
2.2.10 Statistical analysis 17
2.3 Results 18
2.3.1 HA promotes bone marrow MNC adhesion and proliferation 18
2.3.2 HA modulates bone marrow MNC differentiation, upregulates paracrine factor gene expression and reduces MNC apoptosis 21
2.3.3 HA/MNC injection reduces cardiomyocyte apoptosis in vivo 27
2.3.4 HA/MNC treatment reduces the inflammatory response after MI 27
2.3.5 The combined HA/MNC injection improves heart function after MI 30
2.3.6 HA/MNC injection reduces scar formation and does not induce chondrogenesis 30
2.3.7 HA/MNC injection promotes angiogenesis and arteriogenesis after infarction 37
2.4 Discussion 44
2.5 Summaries and Future Direction 49
Chapter 3 Injection of autologous bone marrow cells in hyaluronan hydrogel improves cardiac performance after infarction in pigs 50
3.1 Background 50
3.2 Materials and Methods 52
3.2.1 Experimental Animals 52
3.2.2 Induction of Myocardial Infarction, and HA and MNC Administration 52
3.2.3 Bone Marrow MNC Isolation, Purification, and DiI Fluorescent Dye Labeling 54
3.2.4 Echocardiography 54
3.2.5 Hemodynamics 54
3.2.6 Infarct Size, Length, and Area 55
3.2.7 Collagen Deposition and Wheat Germ Agglutinin Staining 55
3.2.8 Immunohistochemistry 56
3.2.9 Statistical Analysis 56
3.3 Results 58
3.3.1 Combined HA/MNC Injection Elevates Cardiac Function, Thickens the Interventricular Septum, and Prevents Ventricular Remodeling After MI 58
3.3.2 Combined HA/MNC Injection Improves Hemodynamics after MI 61
3.3.3 Combined HA/MNC Injection Reduces Collagen Accumulation and Pathological Hypertrophy in Areas Remote from the Infarct 64
3.3.4 Combined HA/MNC Injection Increases Implanted Cell Retention and Neovascularization 68
3.4 Discussion 72
3.5 Summaries and Future Direction 75
Chapter 4 Conclusion 76
References 77
Curriculum Vitae 98
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