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研究生： 張明曜
Chang, Ming-Yao
論文名稱： 利用生物水膠結合細胞療法改善心肌梗塞後心臟功能表現的轉譯研究
Combined hydrogel and cell therapy improves cardiac performance after infarction in pigs-- Translational approaches
指導教授： 張志涵
Chang, Chih-Han
共同指導教授: 謝清河
Hsieh, C.H. Patrick
學位類別： 博士
Doctor
系所名稱： 工學院 - 生物醫學工程學系
Department of BioMedical Engineering
論文出版年： 2014
畢業學年度： 102
語文別： 英文
論文頁數： 101
中文關鍵詞： 自體骨髓細胞 、單核球細胞 、人類臍帶血單核球 、奈米纖維水膠 、玻尿酸水膠
外文關鍵詞： autologous bone marrow cells, mononuclear cells, human umbilical cord blood mononuclear cells, nanofiber, hyaluronan
相關次數： 點閱：112  下載：1 
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    • 心血管疾病位居全球十大主要死因首位，也是國人前十大死因第二名。心肌梗塞後造成心肌細胞死亡，最後導致心臟衰竭死亡。然而心肌組織是一個再生能力極低的器官，過去幾年研究發現自體骨髓細胞 (autologous bone marrow cell)治療心肌梗塞是一個具有潛力的治療方法。但臨床研究結果顯示細胞治療介入的時間點 (therapeutic time window) 以及細胞品質 (cell quality ) 對於治療效果有極大關係。除此之外，心臟是一個持續收縮的環境，造成植入的細胞停留率低，這是治療心肌梗塞必須去克服的一大課題。生物組織工程透過工程概念來解決生物醫學上所遇到的障礙，水膠 (hydrogel) 是一種親水性材料，是一個富含水分的環境能讓細胞或藥物達到一個良好的傳遞。因此，本研究將根據治療時間點以及細胞品質兩大主軸同時結合生物組織工程的概念，探討最佳治療心肌梗塞的方式。
    本研究將分為兩大部分，第一部份針對治療時間點進行研究。我們利用奈米纖維水膠 (nanofiber) 分別混合不同時間點的自體骨髓單核球細胞(心肌梗塞後1天, 4天 及 7天)治療急性心肌梗塞豬隻心臟。我們發現在擁有相同的細胞停留率時，早期介入能有效地降低心肌梗賽後疤痕組織 (scar tissue) 以及避免並改善心臟功能異常。同時也發現在心肌梗塞後7天所取得的骨髓細胞在分化能力較早期的差，顯示在心肌梗塞後損害了骨髓細胞的修復能力，進而影響到治療心肌梗塞的效果。因此，在第二部分研究，使用人類臍帶血單核球細胞 (human umbilical cord blood mononuclear cells)，這是一個健康來源的細胞，同時混合生物相容性高的玻尿酸水膠 (hyaluronan hydrogel) 來提升細胞停留率以及促進血管新生。我們預期人類臍帶血單核球， 擁有較好的細胞修復能力來改善心肌梗塞治療效果。研究結果顯示急性心肌梗塞後1天，單純植入人類臍帶血單核球細胞在心肌梗塞後兩個月能保護心臟功能流失; 然而，混合玻尿酸水膠與人類臍帶血單核球細胞提高了細胞停留於心肌梗塞區域，同時也改善了心臟收縮與舒張功能並促進更多的血管新生。
    本研究證明心肌梗塞後心臟組織受損程度以及細胞品質同時影響治療結果。因此，我們認為心肌梗塞疾病患者接受自體骨髓細胞移植時，細胞的修復能力可能受到疾病的影響細胞修復受損心肌組織，進而降低了治療效果。利用人類臍帶血單核球能改善自體骨髓細胞治療上的限制。然而，細胞療法結合玻尿酸水膠概念提升在臨床治療的價值與潛力。希望未來能透過更多研究將此技術發展成熟，實際改善心肌梗塞患者的生活品質。

    Cardiovascular disease is the first of top ten leading causes of death in the world; it is also the second of top ten leading causes of death in Taiwan. The death of myocardial cells after myocardial infarction will finally lead to heart failure. However, myocardial tissue is an organ with extremely low regenerating capacity. Research over the past few years suggested that autologous bone marrow cells have great potential in myocardial infarction treatment. Results of some clinical research indicated that cell therapy does not have significant cardiac functional improvement. This result may be largely related to therapeutic time window and cell qualities. In addition, the contraction of hearts results in the low cell retention of transplanted cells. It also poses a major challenge in the development of myocardial infarction treatment. Hence, this study will introduce the concept of tissue engineering to discuss the best myocardial infarction treatment from the view of therapeutic time window and cell qualities.
    This study is divided into two sections. The first section focuses on the discussion of therapeutic time window. Mixtures of nanofibers and autologous bone marrow mononuclear cells with different therapeutic time windows (1, 4 and 7 days after myocardial infarction) are used to treat acute myocardial infarction in pigs. The result shows that when hearts have same cell retention, early involvement can efficiently decrease their scar tissue after myocardial infarction. It can also prevent and improve cardiac dysfunction. Meanwhile, the result also indicates that bone marrow cells which were obtained 7 days after the myocardial infarction have poor differentiation capacity compared with cells obtained earlier. The study demonstrated that myocardial infarction impaired the repair capacity of bone marrow cells and then have a negative effect on myocardial infarction treatment. Therefore, the second section of the study concentrates on discussing the combination which is composed of human umbilical cord blood mononuclear cells (which were acquired from health sources) and high biocompatible hyaluronan be applied on increasing cell retention. We expect human umbilical cord blood mononuclear cells have better repair capacity to improve the efficiency of myocardial infarction treatment. The study result shown that only transplant umbilical cord blood mononuclear cells to hearts one day after acute myocardial infarction, these cells can prevent the loss of cardiac functions. It is also worth pointing out that after acute myocardial infarction, cells which mix with hyaluronan and umbilical cord blood mononuclear cells improve systolic and diastolic function and promote capillary density.
    This research proves that the damage degree of heart tissue and the repair capacity of cells after myocardial infarction both affect treatment outcomes. Thus, we believe that when myocardial infarction patients receive autologous bone marrow cells transplantation, their disease which may have a bad influence on the repair capacity of cells in repairing damaged myocardial tissue will then decrease the treatment efficacy. The application of human umbilical cord blood mononuclear cells can improve treatment limitations of autologous bone marrow cells. There is a great possibility of applying the therapy of combining cells and hyaluronan in clinical treatments. We believe this technique will be fully mature through the development of future studies and research. With the help of the mature technique, the life quality of myocardial infarction patients will be truly enhanced.

    Abstract I 摘要 IV 誌謝 VI Index of Contents VII Index of Figures XI Chapter 1. Introduction 1 1.1 Myocardial infarction 1 1.2 Current therapeutic strategies for MI 1 1.3 Cell therapy in myocardial regenerative medicine 2 1.3.1 Skeletal myoblasts 2 1.3.2 Embryonic stem cells 3 1.3.3 Endogenous cardiac stem cells 4 1.3.5 Bone marrow cells 4 1.3.6 Human umbilical cord blood cells 5 1.4 The challenges of cell therapy in myocardial regeneration 6 1.5 Tissue engineering is a promising approach for myocardial regeneration 7 Chapter 2. Hypothesis and Specific aims 10 2.1 Hypothesis for project 1 10 2.2 Specific aims for project 1 10 2.3 Hypothesis for project 2 10 2.2 Specific aims for project 2 11 Chapter 3. Project 1: The time window for therapy with peptide nanofibers combined with autologous bone marrow cells in pigs after acute myocardial infarction 12 3.1 Background 12 3.2 Materials and methods 13 3.2.1 Experimental Animals 13 3.2.2 Autologous bone marrow mononuclear cell collection and DiI labeling. 14 3.2.3Myocardial Infarction and treatment 15 3.2.4 Echocardiography 16 3.2.5 Hemodynamics 16 3.2.6 Ratio of scar tissue and collagen content 17 3.2.7 Bone marrow cell isolation after myocardial infarction 17 3.2.8 Immunohistochemistry and fluorescence microscopy 18 3.2.9 TUNEL assay 18 3.2.10 Statistical analysis 19 3.3 Results 20 3.3.1Cardiac morphology and function worsens at later time points post-infarction. 20 3.3.2 NF/MNC protects myocardial function depending on the injection time. 22 3.3.3 NF/MNC injection at early time points post-MI decreases infarct size and prevents cardiac fibrosis. 26 3.3.4 NF/MNC injection increases transplant cell retention after MI 30 3.3.5 Early stage NF/MNC injection increases capillary and arteriole densities at the border zone. 33 3.3.6 Acute myocardial infarction changes bone marrow cell composition and decreased endothelial differentiation capability. 36 3.4. Discussion 39 3.5 Conclusion 42 3.6 Summary and future direction 43 Chart 4. Project 2:Injection of human cord blood mononucler cells along with hyaluronan hydrogel improves cardiac repair after myocardial infarction in pigs 44 4.1 Background 44 4.2 Materials and methods 46 4.2.1 Experimental animals 46 4.2.2Isolation human cord blood MNC cells and DiI labeling 47 4.2.3 HA hydrogel prepare 47 4.2.4 Myocardial infarction and treatment 48 4.2.4 Immunosuppression protocol 49 4.2.5 Echocardiography 49 4.2.6 Hemodynamics 50 4.2.7 Ratio of scar tissue and collagen content 51 4.2.8 Immunohistochemistry and fluorescence microscopy 51 4.2.9 Statistical Analysis 53 4.3 Result 54 4.3.1 Inject HA combine CB-MNC improved myocardial function after 2 month myocardial infarction 54 4.3.2Inject HA with CB-MNC improved the hemodynamics after 2 month myocardial infarction 57 4.3.3 Inject HA with CB-MNC decreased scar size and prevented the wall thinning at infarct area after 2 month myocardial infarction 59 4.3.4 Injection of HA hydrogel with CB-MNC cells increases transplanted cell retention after 2 month myocardial infarction 62 4.3.5 Injection of CB-MNC with HA increase capillary and arteriole density in the per-infarct area after 2 month myocardial infraction 64 4.3.6Transplanted CB-MNC with HA increase differentiate into ECs, but not SMAs 67 4.3.7 CD3 positive cells were detected in the cell injection area 70 4.4 Discussion 71 4.5 Summary and future direction 74 Chapter 5.Conclusion 75 References 77 Curriculum vitae 99

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