臺灣博碩士論文加值系統

統計結果顯示心臟衰竭是世界上的主要死因，這是由於心肌細胞增生能力低落而使得心臟再生能力有限所導致。心肌梗塞是造成的心臟損傷的原因之一，過程中大量的心肌細胞死亡以及疤痕組織的形成導致心臟功能永久的破壞，因此如何防止心肌細胞的死亡或是促進其增生變得極為重要。研究發現非哺乳類脊椎動物的心臟具有再生能力，經由實驗性切除部分心臟，在傷口附近可偵測到心肌前驅細胞出現，似乎暗示著新生的心肌細胞可能是由心肌前驅細胞分化而成。在2006年，日本學者Yamanaka發現4種對維持胚胎幹細胞多潛能相當關鍵的基因(Oct4、Sox2、Klf4和c-Myc) 可誘導成熟的老鼠纖維細胞回到多潛能性幹細胞的狀態，簡稱誘導性多潛能幹細胞(iPS cells)。根據這項令人驚訝的發現，我們假設利用iPS誘導基因以及早期心肌的標誌基因可以促進分化完全的心肌細胞逆分化(reprogramming)或增生。
為了增加心肌細胞轉染(transfection)效率，我們利用慢病毒 (lentivirus) 載體攜帶目標基因 (Oct4、Sox2、Klf4、c-Myc、Isl1和Tbx5)進行心肌細胞的生長測試。以碘化丙錠(propidium iodide)染色法分析，發現單獨表達Oct4就足以增加心肌細胞的細胞週期進程。此外，利用反轉錄聚合酶連鎖反應(reverse transcription-polymerase chain reaction)、免疫轉印法 (immunoblotting)以及細胞免疫染色(immunocytochemistry)分析，我們也進一步發現Oct4可誘導細胞有絲分裂相關調控因子cyclin A2、cyclin B1、Aurora B、Survivin以及磷酸化組織蛋白H3(phosphor-histone H3)的表現，並可觀察到心肌細胞進行核分裂(karyokinesis)和細胞質分裂(cytokinesis)，且這個調控作用是透過Akt不相關的訊息路徑。總結以上研究，我們發現iPS的誘導因子-Oct4非常有潛力去促進心肌細胞再生，但是Oct4在老鼠體內是否具有相同效果，還需要進一步研究。

Congestive heart failure is the primary cause of death in the world. The limitation of heart regeneration has been ascribed to the low degree of cell mitosis in cardiomyocytes. Cardiac injuries, such as myocardial infarction, cause cardiomyocyte death and scar tissue displacement, leading to irreversible functional impairment. How to prevent apoptosis or promote proliferation of cardiomyocytes is thus important. Non-mammalian vertebrate heart has regenerative capacity, and may occur through cardiac progenitor cell differentiation. In 2006, Yamanaka’s group reported the use of four factors (Oct4, Sox2, Klf4, and c-Myc), which are crucial to pluripotent maintenance on embryonic stem cells, to reprogram mouse fibroblasts into induced pluripotent stem (iPS) cells. Base on Yamanaka’s idea, we try to use iPS-inducing factors and early cardiac markers to promote the reprogramming and/or proliferation of fully differentiated cardiomyocytes.
First, we established the lentivirus gene delivery system to enhance cardiomyocyte transfection efficiency. Using propidium iodide staining, we found that only Oct4 overexpression promoted cardiomyocyte proliferation. Additionally, we examined cell cycle related gene expression by RT-PCR and immunoblotting, and demonstrated that cyclin A2, cyclin B1, Aurora B, and phospho-histone H3 (H3P) were induced upon Oct4 expression. Furthermore, we observed Oct4-transduced cardiomyocytes undergoing karyokinesis and cytokinesis by staining cell mitosis markers such as H3P, AuroraB and Survivin. Oct4 was observed to co-exist with Ki-67 in the nucleus. Therefore, it is likely that Oct4 promotes cardiomyocyte proliferation by regulating cell cycle related molecules. In accordance with our immunoblotting data, this regulation probably was through Akt independent pathway. In summary, we found that the iPS factor Oct4 has the potential to promote cardiomyocyte proliferation. These preliminary data provide an attractive method to treat heart diseases.

Abstract in English ……………………………………… I
Abstract in Chinese …………………………………………III
Acknowledgement ………………………………………………………IV
Index of tables …….……………………… VII
Index of figures …..………………………VIII
Chapter 1: Introduction ………………………………………………………1
1.1 Congestive heart failure ………………………………………1
1.2 Current therapeutic strategies in heart failure ……………………1
1.3 The obstruction of heart regeneration ………………………………………………2
1.4 The potential of cardiomyocytes proliferation ……………3
1.5 Cardiac stem cells ……………………………………………………………………4
1.6 Cell nuclear reprogramming ………………………………………………………….5
1.7 The candidate factors for cardiac reprogramming ……………………7
Chapter 2: Materials and methods ……………………………………………………11
2.1 Cell culture …………………………………………………………………………..11
2.2 Plasmids ……………………………………………………………………………..11
2.3 Transfection, Lentivirus particle preparation and infection ………12
2.4 Reverse transcription-polymerase chain reaction (RT-PCR) ………………13
2.5 Flow cytometry ………………………………………………………………………14
2.6 Antibodies ……………………………………………………………………………14
2.7 Immunoblotting ………………………………………………………………………15
2.8 Immunocytochemistry ……………………………………………………………….15
2.9 Statistical analysis ……………………………………………………………………16
Chapter 3: Results ……………………………………………………………………....20
3.1 Construction and expression of candidate factors in cardiomyocytes ……………….20
3.2 Only Oct4 expression promotes cell cycle progression in cardiomyocytes ………….20
3.3 Oct4 overexpression regulates genes critical for mitosis in cardiomyocytes ………...21
3.4 Oct4 overexpression promoted neonatal cariomyocytes proliferation in vitro ……….21
3.5 Oct4-enhanced cardiomyocyte proliferation probably was through Akt-independent signaling pathway……………………………………………………………………..22
Chapter 4: Discussion .…………………………………………………………………..32
References ………………………………………………………………………………..36
About the author ………………………………………………………………………...45

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