臺灣博碩士論文加值系統

為了挑戰嚴重的心血管疾病，內皮前軀細胞正廣泛的進行中。然而，要想成功的運用內皮前軀細胞做治療，我們必須先對內皮前軀細胞的生物功能做全盤了解，我們在研究中試圖去探討與內皮前軀細胞純度、生物功能、動脈硬化潛力相關的因素。總共有73位新診斷有冠心病的病人及24位控制組正常人加入研究。在培養內皮前軀細胞共十代的研究中，我們探討代數與純度、生物功能、動脈硬化潛力的相關性，我們也探討動脈硬化風險因子與純度、生物功能、動脈硬化潛力的相關性。第三代到第五代的內皮前軀細胞與較老的代數相比，其純度較高、生物功能較好(一氧化氮的生成及管狀結構的形成)、動脈硬化潛力較差 (p<0.05)。在具焦在第三代內皮前軀細胞的研究中發現，具有動脈硬化風險因子較多的病人，以及那些已診斷有冠心病的病人，他們的內皮前軀細胞純度較差、生物功能較差(一氧化氮的生成及管狀結構的形成)、動脈硬化潛力較強 (p<0.05) 。另外，具有糖尿病、高血壓的病人，以及那些已診斷有冠心病的病人，他們的內皮前軀細胞動脈硬化遣力早已活化。有趣的是 Atorvastatin的使用可幫助那些已診斷有冠心病的病人，改善他們的內皮細胞一氧化氮合成酶的功能 (p<0.01)。結論是，代數和動脈硬化風險因子的多寡與內皮前軀細胞純度、生物功能、動脈硬化潛力非常相關。對具有多項動脈硬化風險因子的人，如果要應用其內皮前軀細胞做治療，必須要先評估其生物功能，並且適時給予處理。
平滑肌前軀細胞同時扮演了導致動脈硬化的好壞兩面，為了要釐清平滑肌前軀細胞在動脈硬化所扮演的角色，我們必須要研發出他們的細胞表面標記。我們使用基因陣列表現分析法去研發出平滑肌前軀細胞的細胞表面標記。實驗發現 PDGFR-alpha、CPM、 RAMP1、CA12、LRP1 是平滑肌前軀細胞專一性極高的五個細胞表面標記，調節平滑肌前軀細胞的移行、細胞外基質的形成、抗缺氧力、和抗發炎力。在動物實驗中，打入動物體內的人類週邊血單核球細胞，發現可分化成動脈硬化上的平滑肌細胞，這些平滑肌細胞都表現PDGFR-alpha、CPM、 RAMP1、CA12、LRP1。基於這些發現，我們發展了一個記數週邊血平滑肌前軀細胞的方法。我們發現，於不穩定心絞痛病人週邊血平滑肌前軀細胞的數目遠高於那些心血管正常的人。 而於急性心肌梗塞的病人，記數週邊血平滑肌前軀細胞的方法也具有相當的專一性。結論，各種源自週邊血的平滑肌前軀細胞的細胞表面標記，也同時具有各種與動脈硬化相關的功能。記數週邊血平滑肌前軀細胞的方法也提供了一個研究動脈硬化的平台。

Endothelial colony-forming cells (ECFCs) are undergoing extensive investigations to tackle certain deliberating cardiovascular diseases. However, the success of this approach depends on a thorough understanding of ECFC biology. This study sought to determine the factors associated the purity, biological function and activation potential of ex vivo expanded ECFCs. Seventy-three patients with newly diagnosed coronary artery disease (CAD) and 24 controls were studied. ECFCs were cultured for up to 10 passages to investigate changes in and the impact of coronary risk factors on ECFC biological functions and the atherogenic potential. Passage 3 to 5 of ECFCs exhibited higher endothelial phenotype expression and better biological functions in terms of nitric oxide secretion and tubular formation, but lower activation potentials, compared to later passages (P <0.05). Studies on passage 3 showed that endothelial phenotype expression and biological functions were impaired, and the activation potentials of the ECFCs were significantly upregulated in subjects with coronary risk factors and especially those with CAD (P<0.05). Furthermore, ECFCs were already activated before inflammatory stimulation in subjects with diabetes mellitus, hypertension and CAD. Atorvastatin upregulated the endothelial nitric oxide synthase expression of ECFCs in CAD patients (P<0.01) although not up to the baseline level of controls. In conclusion, the passage number and a variety of coronary risk factors were associated with the purity, biological function, and activation potential of ex vivo-expanded ECFCs. Functional assessments and manipulations of ECFCs have to be pursued in patients with extensive risk factors.
Smooth muscle progenitor cells (SMPCs) were intriguingly shown to act as a double-edged sword in the pathogenesis of atherosclerosis. To fully clarify the roles of SMPCs in atherosclerosis, a distinct panel of SMPC surface markers is mandatory to be developed. Microarray gene expression analyses were used to discover potential surface markers of SMPCs. In vitro and in vivo experiments documented that PDGFR-alpha, CPM, CA12, RAMP1, and LRP1 were 5 specific surface markers, regulating various SMPC functions including migration, extracellular matrix formation, resistance to hypoxia, and anti-inflammation. In SCID/NOD mice after femoral arterial wire-injury, injected human peripheral blood mononuclear cells contributed to substantial amount of neointimal alpha-smooth muscle actin-positive cells, co-expressing PDGFR-alpha, CPM, CA12, RAMP1, and LRP1. Based on these markers, a novel quantification assay was developed to enumerate circulating early SMPC (SMPCe). SMPCe numbers were higher in patients with unstable angina compared to those with normal coronary angiograms. In patients with acute ST-elevation myocardial infarction, different patterns of serial SMPCe changes were noted, related to different clinical presentations. In conclusion, surface markers of heterogeneous SMPCs exhibit various functions associated with atherosclerotic pathophysiology. Quantification of surface marker-defined SMPCs provides a platform for studying SMPCs in cardiovascular diseases.

目 錄


一. English Abstract 1
二. Chinese Abstract 3
三. List of Abbreviations 5
四. Introduction 7
五. Materials and Methods 25
六. Results 38
七. Discussion 48
八. Conculsion 57
九. Perspectives 58
十. References 59
十一. Figures and Tables 75
十二. Appendix 102
十三. Publications 102

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