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研究生：	甘宗旦 Kan, Chung-Dann
論文名稱：	宿主年齡與不同類型成體幹細胞對心臟細胞治療法的影響探討 Cardiac Cellular Therapy – Host Age and Adult Stem Cell Types Factor Analysis
指導教授：	楊友任 Yang, Yu-Jen
共同指導教授:	羅傳堯 Luo, Chwan-Yau
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2010
畢業學年度：	98
語文別：	英文
論文頁數：	101
中文關鍵詞：	心臟、細胞治療、老年、細胞類型
外文關鍵詞：	Heart, Cell therapy, Aged, Cell types
相關次數：	點閱：110 下載：3
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儘管近年來對心臟疾病在心血管藥物方面有許多重大的突破發展；但在全世界，次發於心肌梗死後的鬱血性心臟衰竭，仍然是一個棘手的醫療健康問題。移植具有潛在收縮能力的外源性的細胞（心肌細胞治療術）至心臟，期望增加心肌收縮能力和整體心臟功能的治療策略，在1990年代初期被提出作為一個治療心臟衰竭的可能方針。發展至今，心肌細胞治療術已可由心肌直接注射，經血管由心臟內注射，經靜脈注射，或冠狀動脈直接注入心臟等各種方式，而達成移殖細胞的目的。數種類型的細胞也被證明可有效預防心室擴張，改善心臟功能。雖然大多數的臨床前研究皆被發表，細胞移植可改善整體和區域性的心臟功能，防止心室重塑後的心臟擴張，和保護心肌損傷後的收縮功能。然而，由於生體系統的複雜性及臨床的安全需求，臨床前動物研究和實際的臨床應用可能會是存在著明顯的不相符性。
在全面性的回顧心肌細胞治療術的各種類型細胞的歷史發展後，許多臨床應用的實際問題逐漸被提出需重新思考與檢視，這些問題包括了：什麼是最好的細胞選擇類型，何時是最適當的植入時間，如何達成最有效移殖方式，多少細胞才是有效的劑量，達到心臟功能改善的相對機轉，和宿主條件的差異性。

由於大多數被證實具改善心肌梗死後心臟功能的心肌細胞治療術的動物研究，都是經由移植胎兒或年輕動物的細胞至年輕的宿主。相反的，真正的臨床研究所使用的來源細胞及宿主，則是應用於可能具有許多併發症的老年人。因此，本實驗的第一部分將比較不同年齡的細胞供應者的生長影響特點，和其對不同年齡宿主的影響，以確定年齡對心肌細胞治療術的真實影響性。實驗的結論是經由骨骼肌幹細胞的移殖，年輕宿主的確可經由心肌細胞治療術較老年宿主獲得較明顯的心臟功能改善成效。老年的因素的確會降低心肌細胞治療術所帶來的好處。

另外，由於大多數的研究皆是利用某一種細胞類型來探討心肌細胞治療術的成效。所以本實驗的第二部分將藉由比較骨骼肌成肌細胞，骨髓基質幹細胞，平滑肌細胞的體外培養，與探討這些細胞於生體心臟對受損心臟功能的影響，希望能對這些成體幹細胞作較詳盡的比較與探討。實驗的結論是總體細胞的存活率和血管新生能力的總和效果，對治療缺血性心臟病的心肌細胞治療術具有相當重要的影響性。骨骼肌成肌細胞，骨髓基質幹細胞，平滑肌細胞皆可表現有血管內皮生長因子和幹細胞生成因子，並進而促進血管生成，都具有心肌細胞治療術改善心室功能的能力。

雖然目前對心肌細胞治療術用以改善心臟功能的確切機制還沒有完全了解，仍待多方的研究加以釐清。然而，藉由探討某些影響因素對心肌細胞治療術的真實影響，也許可以幫助我們釐清與解釋基礎研究和臨床應用間，不完全相符的一些問題，並可協助解決臨床應用的難題。在本實驗研究，藉由不同年紀宿主與不同移殖細胞類型的體外細胞培養與生體內移植比較，發現：宿主的年齡，不同種類細胞的特徵，和不同種類細胞其生存和內分泌作用的總和影響，對心肌細胞治療術都具有其特定的角色扮演與影響程度。

Despite many breakthroughs in cardiovascular medicine, congestive heart failure (CHF) secondary to ventricular remodeling following myocardial infarction continues to be a serious medical health problem worldwide. Transplantation of exogenous cells (cellular cardiomyoplasty) with the inherent capability of forming contractile elements was proposed in the early 1990s as a potential treatment strategy to increase contractility and cardiac performance, and as a potential cure for the syndrome of heart failure. Cardiac cellular therapy has been achieved by delivering the cells into the infarct region and borderzone by transepicardial, transendocardial, or transvenous injection, or by intravenous or intracoronary infusion. Several cell types have also been shown to be effective in preventing ventricular dilatation and improving ventricular function. Although most preclinical studies have demonstrated that cell transplantation improves global and regional cardiac function with respect to ventricular remodeling, prevention of cardiac dilatation and preservation of systolic function after myocardial injury. However, owing to the significant complexity of the biological system and the required safety profiles for clinical application, discrepancies between preclinical and clinical results have been observed.

From the completely literatures reviewing of the developing histories and clinical applications of cardiac cellular therapy by various cell types, several important practical considerations are raised, including: best cell type choice, appropriately implanting timing, effectively deliver route, effective delivering cell dose, corresponding functional improving mechanisms, and host conditions.

Owing to most of preclinical investigations of cardiac cellular therapy, which demonstrated improved ventricular function after a myocardial infarction, involve the implantation of cells from fetal or young donor animals into young recipients. And, the initial clinical trials, in contrast, have utilized cells derived from and implanted into older individuals with extensive comorbidities. Therefore, the first part of project compared the effects of donor age on the growth characteristics of SKMCs, and the effects of recipient age on the cardiac response to SKMC transplantation to determine the influence of age on the response to cardiac cellular therapy. The conclusion was that cardiac functional improvement was significantly greater in young recipients of SKMC transplantation following coronary ligation. Advanced age may diminish the functional benefits of cardiac cellular therapy.

Because most studies have just focused on one cell type, the second part of project aimed to compare characteristics of skeletal myoblasts (SKMCs), bone marrow stromal stem cells (BMSCs), and smooth muscle cells (SMCs) and their in-vivo effects on cardiac function after myocardial injury to figure out which is the suitable adult stem cells in clinical applications. And then, the results were that the summation effect of cell survival and neovasculogenesis are important for successful cell therapy of the ischemic heart. SKMCs, BMSCs and SMCs expressed vascular endothelial cell growth factor and stem cell factor and promoted vasculogenesis.

The exact mechanisms corresponding for cardiac cellular therapy still are not well figured out and needs lot efforts to work them out. However, understanding the numerous impact factors for the true effects of cardiac cellular therapy might help us to explain and solve the basic-clinical inconsistent questions. From this experiment, some important factors, such as: recipient age, different cellular characteristics, and their survival and paracrine summation effects were explored and identified to have significant roles on cardiac cellular therapy.

English Abstract	5 
Chinese Abstract	7
Acknowledgements	9
Chapter 1  Cellular Therapy for Heart Failure -- Current Status & New          Trends in Cardiovascular Surgery 
  1.1. Introduction	10
  1.2. Historical Development of Cellular Cardiac Regeneration	12
  1.3. Current Research of Cell Therapy	20
  1.4. Clinical Application of Cellular Therapy	25
  1.5. Retrieving and Interpreting between the Studies and Clinical Results	27
  1.6 Conclusion	29
  1.7 Intending Work of PhD project	30
Chapter 2  Recipient Age Determines the Functional Improvement           Achieved by Skeletal Myoblast Transplantation 
  2.1 Introduction
31
  2.2 Materials and Methods	31
     2.2.1 Research animals	31
     2.2.2 Rat skeletal myoblast cultures	31
     2.2.3 Cell growth study	32
     2.2.4 Immunohistochemical staining	32
     2.2.5 Myocardial infarction	33
     2.2.6 Cell preparation for transplantation	33
     2.2.7 Cell transplantation	33
     2.2.8 Measurement of cardiac function	34
     2.2.9 Morphological and histological analyses	35
     2.2.10 Statistical analyses	35
  2.3 Results	36
     2.3.1 In Vitro Study	36
     2.3.2 In Vivo Study	36
  2.4 Discussion	39
Chapter 3  Different Neovasculogenic Potential and Survival Rates Affect Efficacy of Allogenic Cell Therapy- Comparison of Three Different Adult Cell Populations
  3.1 Introduction	43
  3.2 Methods	45
     3.2.1 Animals	45
     3.2.2 Cell isolation and culture	45
     3.2.3 Cell proliferation assay	46
     3.2.4 Assessment of hypoxia induced by H2O2 treatment	46
     3.2.5 Assessment of hypoxia in a hypoxic chamber	46
     3.2.6 Quantification of VEGF and SCF expression	46
     3.2.7 Infarction model	47
     3.2.8 Cell preparation and transplantation	47
     3.2.9 Assessment of cardiac function	47
     3.2.10 Tissue collection and analysis	48
     3.2.11 Quantification of cell survival	48
     3.2.12 Statistical analysis	48
  3.3 Results	49
     3.3.1 Comparison of in vitro cell morphology and proliferation rate	49
3.3.2 In vitro apoptosis, cell viability and VEGF protein expression	49
     3.3.3 Cell survival after transplantation	49
     3.3.4 Heart tissue VEGF and SCF protein expression	50
     3.3.5 Analysis of in vivo cardiac function	50
     3.3.6 Vasculogenesis of the infarct	50
  3.4 Discussion	51
  3.5 Conclusions	53
Chapter 4 Conclusion	54
Chapter 5 Future Work	56
Reference List	57
Tables	74
Figures	77
List of thesis related publications	95
Curriculum Vitae	96
Grants	97
Publications	99
	
LIST OF TABLES	
Table 1  Short Summary of Clinica Application Study Results	74
Table 2  Cardiac Function by Echocardiography	75
Table 3  Change of cardiac function following cell transplantation.	76
	
LIST OF FIGURES	
Figure  1.  Possible mechanisms of cardiac cellular therapy	77
Figure  2.  Techniques for cell transplantation delivery	78
Figure  3.  Morphology of skeletal myoblast cells (SKMCs) in culture and cell proliferation abilities comparison	79
Figure  4.  Skeletal myoblast cell markers staining and myotubes formation abilities comparison. 	80
Figure  5.  Survival rates comparison. 	81
Figure  6.  Cardiac function by echocardiography.	82
Figure  7.  Cardiac function by pressure-volume catheter.	83
Figure  8.  Cellular density comparison and evidence for implantated cell survival.	84
Figure  9.  Vasculogenesis comparison.	86
Figure 10.  Matrix preservation comparison.	87
Figure 11.  Different cell types’ proliferation rates comparison.	88
Figure 12.  In vitro apoptosis and vascular endothelial growth factor (VEGF) expression.	89
Figure 13.  Cell survival comparison by PKH26 staining.	90
Figure 14.  Cell survival comparison by real-time polymerase chain reaction.	91
Figure 15.  In vivo growth factor expression as determined by enzyme-linked immunosorbent assay (ELISA).	92
Figure 16.  Effects of cell transplantation on cardiac function and vasculogenesis comparison.	93

                                    

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