系統識別號 U0026-0202201514275300
論文名稱(中文) 探討循環細胞對心臟修復之貢獻
論文名稱(英文) Contribution of Circulating Cells to Cardiac Repair
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 1
出版年 104
研究生(中文) 吳美芳
研究生(英文) Mei-Fang Wu
學號 S58991340
學位類別 博士
語文別 英文
論文頁數 70頁
口試委員 指導教授-謝清河
中文關鍵字 雙體循環共用系統  循環細胞  融合  分化  免疫細胞 
英文關鍵字 parabiosis  circulating cells  fusion  differentiation  immune cells 
中文摘要 冠狀動脈阻塞將造成心肌死亡並伴隨著強烈的發炎反應產生。近年來研究發現早期發炎反應除了會吸引骨髓中的免疫細胞到達心臟受損的位置,其發炎調控因子也具有啟動心肌再生的能力。此外,有些研究結果亦指出骨隨幹細胞也可能是心肌再生的細胞來源之一。但此一論點仍具爭議,且已有研究結果顯示骨隨幹細胞只能在受損心臟中分化成血液細胞。出現爭議的原因有可能在於目前公認研究方法有缺陷,因而產出不同的結果。
我們先前的研究結果指出由內生性幹細胞參與之心肌再生是在心臟受損後七天內啟動。心臟受損發炎時所生成之前列腺素E2 (prostaglandin E2, PGE2)對於心臟再生具有調控功能,並可以刺激更多的內生性心肌幹細胞分化成心肌細胞。此外,PGE2亦調整心臟受損後三天內的M2巨噬細胞(macrophage)比率。我們先前的研究除了顯示PGE2很有可能透過其EP2受器來調控巨噬細胞,亦暗示探討循環系統中的細胞如何參與心臟修復必需考慮到時間性的問題。因此本篇研究除了探討免疫細胞在心臟修復所扮演的角色,並修改過去的研究方法來重新檢視循環系統中的骨隨幹細胞如何參與在心臟修復。
為了探究循環系統中的幹細胞在心臟修復中所扮演的角色,我們結合了誘導式的細胞血統追蹤(pulse-trace labeling) 和雙體循環共用系統 (parabiosis)來探究其參與修復之機制。結果發現循環系統中的細胞確實會在心臟損傷的位置成為心肌細胞,並表現成熟心肌特有的蛋白質。經由細胞血統追蹤系統,我們更近一步發現循環系統中的細胞會直接分化成心肌細胞,或與其原生的心肌細胞進行融合。相較於先前對於循環系統中的細胞或骨髓幹細胞的認知,我們的結果推翻了之前的論述。除了循環中的幹細胞,此篇研究亦探討延續了先前PGE2的研究,我們運用全身性EP2受器基因缺失之轉殖鼠來探討循環中的免疫細胞如何影響心臟修復。我們發現在缺少EP2受器的情況下,在受損心臟之巨噬細胞的數量有減少的現象,這說明了PGE2可能透過EP2受器來調控心臟受損後的發炎反應。EP2受器缺失除了減低內生幹細胞補充心肌細胞之比率,我們透過超音波檢測心功能也證實其心臟受損後的收縮功能亦受到影響。本篇研究結果指出骨髓來源之細胞,無論是幹細胞或免疫細胞,皆參與在心臟治療的過程。未來更進一步了解這些細胞群如何被調控將能更有效的促進其參與在心臟再生之功能。
英文摘要 Coronary artery occlusion is accompanied by extensive cardiomyocyte death, which subsequently leads to intensive inflammatory response. Accumulating studies have reported that early inflammation is critical for recruitment of immune cells to the injured myocardium and it has been implicated in tissue regeneration. In addition to immune cells, numerous studies have suggested that bone marrow served as a reservoir of stem cell populations for cardiomyocyte repopulation. However, this remains a controversial issue. It is observed that the bone marrow-borne cells can only adopt to the cells of hematopoietic lineage in the injured heart. The controversy may arise from a problematic methodology.
In previous study we discovered that cardiomyocyte replenishment was initiated in 7 days post- myocardial injury. Administration of immune modulator prostaglandin E2 (PGE2) not only promoted endogenous stem cell-mediated cardiomyocyte replenishment but also changed inflammatory microenvironment at day 3 post-infarction by altering percentage of the M2 macrophages. The finding implies that the time point is an important parameter to examine contribution of circulating cells to heart repair. Furthermore, a PGE2-related downstream signal, particularly acting through the EP2 receptor, is involved in cardiac repair by modulating macrophage activities. Therefore the main theme of current study is to examine the role of two distinct circulating cell populations, the bone marrow-borne stem cells and immune cells, in heart repair.
To evaluate the contribution of bone marrow-borne cells in myocardial regeneration, we combined two approaches, pulse-trace labeling and a parabiosis model, to examine the fate of circulating cells in the injured myocardium under normal physiological conditions. In the parabiosis model, we observed scattered circulating cells derived from the parabiotic partner expressed cardiac-specific markers throughout the myocardium. Genetic tracing revealed that circulating hematopoietic cells acquired cardiac cell fate by means of cell fusion and trans-differentiation. In contrast to the previous report that bone marrow-borne circulating cells only adopt hematopoietic cell fate in the injured myocardium, we showed that circulating hematopoietic cells participate in cardiomyocyte regeneration in a mouse model of parabiosis. To examine how PGE2-related immune response contributes to cardiac repair, EP2-deficient transgenic mice were used. In the EP2 knocked out mice we detected a reduction in number of macrophages at day 3 post-infarction, suggesting the EP2 receptor involved in acute inflammatory response. Lineage tracing revealed that EP2 deficiency effectively blocked endogenous stem cell-dependent cardiomyocyte replenishment. Furthermore, cardiac function of EP2 knocked out mice was also impaired.
In conclusion, our findings reveal the contribution of two different bone marrow-borne cell populations, the stem cells and immune cells, in cardiac repair. Detailed mechanistic studies are required to uncover how functions of these cells populations could be modulated to boost their power to repair injured tissue.
論文目次 中文摘要 I
Abstract III
Acknowledgments V
Table of Contents VI
Index of Figures IX
Index of Tables X
List of Abbreviation XI

Chapter 1: Introduction 1
1.1 Heart regeneration 1
1.2 Cell populations for cardiac regeneration 3
1.2-1 Resident cardiomyocytes 3
1.2-2 Heart-resident stem/progenitor cells 5
a. c-Kit+ cardiac cells 5
b. Sca-1+ cardiac cells 6
c. Cardiac side-population cells 7
d. Cardiosphere-derived cardiac stem cells 7
e. Islet-1+ cardiac stem cells 8
1.2-3 Non-heart resident stem cells 9
a. Skeletal myoblast 9
b. Bone marrow-borne cells 10
c. Pluripotent stem cells 11
1.3 Inflammation and tissue regeneration 13
Chapter 2: Rational and Hypothesis 16
Chapter 3: Materials and Methods 18
3.1 Materials 18
3.1-1 Primers 18
3.1-2 Antibodies 19
3.1-3 Chemicals and agents 19
3.2 Methods 20
3.2-1 Animals 20
3.2-2 In Vivo contrast-enhanced microbubble imaging 21
3.2-3 Parabiosis and myocardial injury model 21
3.2-4 Adult cardiomyocyte isolation 22
3.2-5 Immunohistochemical staining 22
3.2-6 Immunocytochemistry and X-Gal staining 23
3.2-7 Cardiomyocyte quantification 23
3.2-8 Flow cytometric analyses 24
3.2-9 RNA extraction and quantitative PCR 24
Chapter 4: Results 25
4.1 Stabilization of cross circulatory system requires 7 to 10 days after surgery 25
4.2 Circulating cells integrated into microvasculature and acquired mature hematopoietic cell fates in injured Heart 29
4.3 Circulation-derived cardiomyocytes integrated into injured myocardium 32
4.4 Circulation-derived cardiomyocytes arisen from cell fusion and transdifferentiation 39
4.5 Stabilized cross circulation is important for acquisition of cardiac fate by circulating cells 44
4.6 Loss of EP2 receptor reduces number of macrophages 47
4.7 EP2 deficiency impairs cardiomyocyte replenishment in the injured myocardium 51
Chapter 5: Discussion 53
5.1 Circulating cells contribute to myocardial
regeneration 53
5.2 Stabilized cross circulation is prerequisite for cardiac cell fate acquisition of hematopoietic ells in injured myocardium 53
5.3 Contribution of cell fusion to tissue repair 54
5.4 Exploring the role of EP2 receptor in post-infarcted myocardium 55
5.4-1 Inflammatory response is perturbed upon loss of EP2 55
5.4-2 EP2 deficiency impairs cardiac regeneration 56
5.5 Clinical implication 57
References 60
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