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系統識別號 U0026-0109201416461800
論文名稱(中文) 前列腺E2在年輕或老年鼠中藉由調控幹細胞達到心肌梗塞後的心肌再生
論文名稱(英文) Prostaglandin E2 regulates stem cell-mediated cardiomyocyte regeneration after myocardial infarction in young and aging mice
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 102
學期 2
出版年 103
研究生(中文) 薛盈彰
研究生(英文) Ying-Chang Hsueh
學號 S58951154
學位類別 博士
語文別 英文
論文頁數 116頁
口試委員 指導教授-余俊強
指導教授-謝清河
召集委員-吳梨華
口試委員-吳華林
口試委員-黃玲惠
口試委員-伍焜玉
口試委員-葉宏一
中文關鍵字 心臟再生  發炎反應  環氧化酶2  前列腺素E2  細胞血統追蹤  老化  幹細胞 
英文關鍵字 cardiac regeneration  inflammation  cyclooxygenase 2  prostaglandin E2  genetic fate-mapping  aged  stem cells 
學科別分類
中文摘要 在人類以及老鼠的成熟心臟中發現多種心肌幹細胞,具有在體外分化成心肌細胞的能力,證明成體心肌幹細胞的存在。當心臟受損時會立刻產生一系列的發炎反應,起先由死亡的細胞釋放出各種cytokines以及chemokine來吸引白血球清除死亡的細胞,接著開始組織再生的路徑,這個過程有利於心臟組織重建,但心肌幹細胞於哪個時間點被活化,或啟動其分化的機制仍然不清楚。近年於多種組織受損研究發現到,七天內的早期發炎反應是啟動組織再生的關鍵,不但具有驅動新生血管的功能,更重要的是能夠活化成體幹細胞分化。心臟受損後的發炎路徑與其他組織類似,但發炎路徑是否調控心肌幹細胞分化則仍未有報導。因此我們將著重於幹細胞修復機制的探討,藉由自然產生的機制找出未來修復心臟的可行辦法,改善現有的治療方式。

本篇研究利用誘導型的細胞血統追蹤系統(Cre-LoxP)來定量內生性心肌幹細胞的效率,我們發現心臟受損後幹細胞的修復於7天內開始10天趨於飽和。在心臟受損的五天之內給予抑制發炎作用的cyclooxygenase (COX)-2抑制劑,將會降低內生性幹細胞修復心臟的能力,相反的給予年輕老鼠COX-2下游生成物prostaglandin E2 (PGE2)將會增加幹細胞修復的效率,並且回復COX-2抑制劑對幹細胞修復的影響。進一步發現到PGE2也可以透過降低老年個體心臟受損後transforming growth factor β-1的表現量,進而回復老年個體喪失的幹細胞修復能力。其機制則是PGE2透過EP2 receptor調控cardiac Sca-1+ cell分化成心肌的能力,並且PGE2能夠改變受損後心臟的微環境使其更有利組織再生,這可能讓年輕或老年老鼠的心臟內的幹細胞更有利存活並分化成心肌。

目前臨床上仍缺乏能刺激內生性幹細胞修復心臟的治療方式,因為過去對再生的機制所知不多,無法設計藥物刺來激內生性幹細胞修復心臟。目前治療方式大多利用開胸或是心導管直接在受損的心臟位置給予藥物或是幹細胞,如此療程確實能改善受損後的心臟功能,但難以持續由相同方式進行治療。透過本篇的研究成果,我們認為PGE2可做為的心臟治療藥物之一,PGE2可以持續經由循環系統給予,調控內生性心臟幹細胞分化成心肌,搭配現存的治療方式一同處理受損的心臟,相信可以增進治療的效果,改善受損後的心功能。
英文摘要 Several types of cardiac stem cells capable of giving rise to cardiomyocytes in vitro have been identified in human and adult mouse hearts, suggesting the presence of cardiac stem cell populations. Following heart injury, cytokines and chemokines are released to recruit white blood cells for clearance of dead cells to assist tissue regeneration. Although this process is beneficial to reconstitution of damaged heart, the time point when cardiac stem cells is activated and how they activity is regulated remain unclear. Accumulating studies have identified that early inflammatory response activated within 7 days post-injury is the key to tissue regeneration. Such early response not only activates angiogenesis but more importantly, it stimulates differentiation of adult stem cells. Whether inflammatory response regulates cardiac stem cell differentiation remains unclear despite heart shares similar inflammatory pathway with other tissues after injury. This study focuses on examining the mechanism of stem cell-dependent tissue regeneration and how this can be translated into clinical application to treat heart diseases.

This study employed Cre-LoxP cell lineage tracing system to quantify the efficiency of endogenous stem cells to replenish lost cells. We discovered that stem cell-mediated repair is activated within 7 days and saturated at day 10 post-heart injury.Administration of cyclooxygenase (COX)-2 inhibitor within 5 days after heart damage could effectively attenuate ability of endogenous stem cells to repair heart. Nevertheless, treatment with the COX-2 downstream product prostaglandin E2 (PGE2) significantly improved efficiency of stem cells to replenish lost cells and restored COX-2-dependent inhibition on stem cell activities. Further investigation revealed PGE2 recovered endogenous stem cell-modulated tissue repair that has been lost in aged heart by lowering expression of transforming growth factor β-1. Detailed examination suggested that PGE2 acted through EP2 to regulate the ability of cardiac Sca-1+ cells to undergo cardiomyocyte differentiation. Furthermore, it modulated the micro-environment of injured heart to aid its regeneration. Such micro-environment may favor survival and differentiation of cardiac stem cells in both young of aged hearts.

Due to limited understanding of the mechanism governing tissue regeneration, a therapy aims at stimulating endogenous stem cells for cardiac repair still lacks. The majority of current therapies involve drug or stem cell delivery via chest-opening or catheterization, which limit the feasibility of cardiac therapies. Results from this study suggest PGE2 could potential be used to treat heart diseases. The most profound advantage of PGE2-based treatment would be that it can be administrated continuously via circulation system to regulate endogenous stem cell activities. In combination with current therapies, the cardiac function of injured heart would be greatly improved.
論文目次 Table of Contents
Abstract I
Abstract in Chinese III
Acknowledgments V
Table of Contents VI
Index of Figures XI
Index of Tables XIV
Chapter 1: Introduction 1
1.1 Heart failure and therapy 1
1.2 Cardiac regeneration 1
1.2-1 Embryonic stem cells (ESCs) 3
1.2-2 Induced pluripotent stem cells (iPSs) 4
1.2-3 Skeletal myoblasts 5
1.2-4 Bone marrow mononuclear stem cells 5
1.2-5 Mesenchymal stem cells 6
1.2-6 Endothelial progenitor cells 6
1.2-7 Adipose-derived mesenchymal stem cells 7
1.2-8 Cardiac stem/progenitor cells 7
a. c-Kit+ cardiac stem/progenitor cells 8
b. Sca-1+ cardiac stem/progenitor cells 10
c. Cardiosphere-derived stem cells 11
d. Isl-1+ cardiac progenitor cells 11
e. Nkx2.5+ cardiac progenitor cells 12
f. Wt1+ cardiac progenitor cells 12
1.3 Cardiac repair by endogenous cardiac stem/progenitor cells 13
1.3-1 Inflammatory response after heart injury 14
1.3-2 Macrophage regulates inflammation post-heart injury 15
1.3-3 Tissue regeneration regulated by Cyclooxygenase (COX)-2/PGE2 pathway 16
1.4 Different approaches to studying the repairing mechanism of an injured heart 17
1.4-1 Bio-compatible materials have been used for heart repair 17
1.4-2 Exogenous delivery of cardiac stem/progenitor cells to treating injured heart 18
1.4-3 Stimulation of cardiomyocyte proliferation for heart regeneration 19
1.4-4 Activation of endogenous cardiac stem/progenitor cells for cardiac repairment. 20
Rational and Hypothesis 22
Specific aims 22
1.Examining the correlation between inflammatory response and the time window of cardiac stem cell-modulated heart repair. 22
2.Investigating the mechanism of PGE2-regulated cardiomyocyte differentiation from cardiac stem cells after heart injury. 22
3.Examining stem cell-dependent heart repair after injury in aged animal model. 22
Chapter 2: Methods and Materials 23
2.1 Mouse breeding 23
2.2 Surgery 23
2.3 Software-based image analysis 23
2.4 Small molecular treatment 24
2.5 GFP+ or β-Gal+ cardiomyocyte counting 24
2.6 Immunohistochemistry and immunofluorescence microscopy 25
2.7 Extraction and preparation of total RNA for quantitative real-time PCR 25
2.8 Flow cytometry, cell isolation, culturing and immunocytochemistry staining 27
2.9 Flow cytometric analysis of macrophages 27
2.10 Data analysis 28
Chapter 3: Early inflammation regulates heart regeneration after injury 29
3.1 Background 29
3.2 Establishment of cell quantification system to evaluate stem cell-dependent tissue repair 29
3.3 Endogenous stem/progenitor cell-mediated cardiomyocyte replenishment is initiated within 7 days post-myocardial infarction 30
3.4 Early COX-2 activity is required for post-infarction cardiomyocyte replenishment 31
Chapter 4: PGE2 activates cardiomyocytes replenishment by regulating Sca-1+ cardiac stem cells and micro-environment after myocardial infarction 43
4.1 Background 43
4.2 The COX-2 downstream produce, prostaglandin E2 (PGE2), promotes cardiomyocyte replenishment after infarction 43
4.3 Sca-1 gene expression is induced in the myocardial infarction heart following PGE2 treatment 44
4.4 PGE2 enhances the cardiac differentiation potential of Sca-1+ cells 45
4.5 PGE2 regulates cardiac Sca-1+ stem cell activity directly through the EP2 receptor 46
4.6 PGE2 inducing Sca-1+ cells differentiation into cardiomyocyte may need niche cells 46
4.7 PGE2 modulates post-infarction inflammatory response in the myocardium 47
Chapter 5: Heart regeneration in aged mice 66
5.1 Background 66
5.2 PGE2 rescues the cardiomyocyte regeneration capacity of aged mice 66
5.3 PGE2 rescues the cardiomyocyte regeneration capacity of aged mice 67
5.4 PGE2 active Sca-1 and c-Kit gene expression in aged mice 67
Chapter 6: Discussion 76
6.1 Early inflammatory response activates tissue regeneration 76
6.2 Using somatic cell fate mapping approach to study stem cell-dependent tissue regeneration 77
6.3 Relationship between PGE2 and tissue regeneration 78
6.4 How PGE2 regulates cardiac Sca-1+ cells for heart repair 79
6.4-1 Regeneration efficiency in EP2 knock out mice 80
6.4-2 PGE2 may not only activate the Sca-1+ cells reside in the heart 80
6.5 How PGE2 regulates Wnt signaling pathway in cardiac stem/progenitor cells 81
6.6 PGE2 not only modulates stem cell activity but also regulates inflammatory microenvironment 82
6.6-1 PGE2 regulates inflammatory micro-environment after heart injury 83
6.6-2 PGE2 changes stem cell niche post-MI 84
6.7 PGE2 may activate stem cells by modulating the microenvironment in aged mice 85
6.7-1 Identifying the source of TGF-β1 is the key issue in the study of aged micro- environment 85
6.7-2 The inflammatory response after MI in young and aged individuals may be different 86
References 88
Curriculum Vitae 115


Index of Figures
Figure 1. The strategy for adult cardiomyocytes fate-mapping 33
Figure 2. Determination of the dose-dependency of Tamoxifen treatment on GFP- and β-Gal- labeling efficiency 34
Figure 3. Tamoxifen Injection causes reversible and transient cardiac functional insufficiency in M/Z mice 35
Figure 4. DAB+ cells were identified using HistoQuest software 36
Figure 5. Replenishment of adult mouse cardiomyocytes by endogenous stem/progenitor cells occurs within 7 days and is saturated on day 10 following infarction 38
Figure 6. Higher dosage of Tamoxifen injection has no effect on cardiomyocyte replenishment after myocardial infarction 40
Figure 7. COX-2-dependent signaling pathway stimulates cardiomyocyte replenishment by endogenous stem/progenitor cells shortly after infarction 41
Figure 8. Early COX-2 signalling pathway is necessary for cardiomyocyte regeneration 42
Figure 9. PGE2 stimulates cardiomyocyte replenishment by endogenous stem/progenitor cells after infarction 48
Figure 10. Expression of inflammatory cytokines acting downstream of PGE2 in the infarcted region of hearts from young mice 49
Figure 11. The number of β-Gal+ cardiomyocytes increases after PGE2 treatment on day 14 post-infarction 50
Figure 12. PGE2 does not alter the GFP labelling efficiency in M/Z mice 51
Figure 13. Gene expression analysis of cardiac stem cell marker genes after myocardial infarction in response to different drug treatments 52
Figure 14. Gene expression analysis of cardiac transcription factor marker genes after myocardial infarction in response to different drug treatments 53
Figure 15. PGE2 augments expression of Nkx2.5 in Sca-1+ cells of injured heart 54
Figure 16. Examination of cardiomyogenic differentiation ability of cardiac Sca-1+ cells after myocardial infarction 55
Figure 17. Sca-1+/α-MHC+ cells neither are detected before tamoxifen labeling and nor arise from cardiomyocyte de-differentiation or fusion 57
Figure 18. The EP2 receptor regulates cardiomyocyte differentiation of Sca-1+ cells 58
Figure 19. PGE2 increases the expression of EP2 receptor after myocardial infarction 60
Figure 20. The expression of EP2 receptor increases in Sca-1+ cells isolated from the infarcted heart after PGE2 treatment 61
Figure 21. In vitro differentiation ability of isolated cardiac cells into cardiomyocytes 62
Figure 22. PGE2 increases the number of M2 type macrophages in the myocardium after injury 64
Figure 23. PGE2 induces IL-10 level after infarction in young mice 65
Figure 24. PGE2 treatment restores cardiomyocyte replenishment in aged mice 69
Figure 25. Gene expression analysis of PGE2-regulated inflammatory cytokines in aged M/Z mice 70
Figure 26. PGE2 induces TGF-β1 level after infarction in aged mice 71
Figure 27. Cardiomyocyte replenishment in aged mice was rescued by PGE2 administration and TGF-β1 singling inhibition 72
Figure 28. PGE2 induces IL-10 level after infarction in aged mice 73
Figure 29. Gene expression analysis of cardiac markers in aged mice after infarction 74
Figure 30. The expression of EP1-4 receptors in Sca-1+ and c-Kit+ cells isolated from the infarcted heart after PGE2 treatment in aged mice 75




Index of Tables
Table 1. List of primers for quantitative or semi-quantitative PCR 26
Table 2. Confirmation of the accuracy of the HistoQuest software-based calculations 36
Table 3. Differences between naked-eye and software-based calculations of DAB+ cells 37
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