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研究生:施佑宗
研究生(外文):Shih, Yu-Tsung
論文名稱:血管細胞與癌細胞調節內皮先驅細胞的移動性與分化潛能之研究
論文名稱(外文):Regulation of Endothelial Progenitor Cells Behavior and Differentiation by Vascular and Tumor Cells
指導教授:裘正健裘正健引用關係
指導教授(外文):Chiu, Jeng-Jiann
口試委員:蕭樑基蔡旻倩傅毓秀陳永祥
口試委員(外文):Siu, Leung-KeiTsai, Min-ChienFu, Yu-ShowChen, Yung-Hsiang
口試日期:2012-03-26
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:156
中文關鍵詞:細胞微環境;內皮先驅細胞;內皮細胞;平滑肌細胞;肝癌細胞; Beta2 整合素;Notch;MIP-3alpha/CCR6 axis
外文關鍵詞:Cellular microenvironmentEndothelial progenitor cellEndothelial cellSmooth muscle cellHepatocellular carcinomaBeta2 integrinNotchMIP-3alpha/CCR6 axis
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血液衍生內皮先驅細胞(Blood-derived endothelial progenitor cells)的招募(recruitment)及分化潛能對於心血管疾病與癌症新生血管之發展具有高度的關聯性,然而細胞微環境(cellular microenvironment)對內皮先驅細胞的潛能特性(differentiation)與可塑性(plasticity)的運用仍未明瞭。目前研究指出三種細胞形式的內皮先驅細胞--CD34+CD31+內皮先驅細胞(circulating EPC, CD34+CD31+ cells)、骨髓系內皮先驅細胞(myeloid-derived EPCs, CFU-EC)與衍生內皮先驅細胞(Outgrowth EPC, ECFC)均被認為在動脈硬化(atherosclerosis)或血管新生(angiogenesis)過程中扮演不同的角色。本研究首先探討內皮先驅細胞與肝癌細胞(hepatocarcinoma cell)共同培養環境下,肝癌細胞對於內皮先驅細胞的分化潛能、趨引性(chemotaxis)以及發炎活性(pro-inflammatory activity)之改變。結果顯示肝癌細胞株Huh7以及Hep3B會刺激骨髓系內皮先驅細胞CFU-EC表現內皮細胞標記蛋白KDR、Flt1、CD31、VE-cadherin,但是卻抑制衍生內皮先驅細胞ECFC的CD31以及VE-cadherin。趨化性實驗證實肝癌細胞株會專一性吸引CFU-EC發生方向性趨引作用(directional chemotaxis),另一方面ECFC卻沒有此現象。同時我們利用細胞素蛋白陣列系統(cytokine protein array)發現肝癌細胞株分泌出高量之細胞趨化激素MIP-3alpha((macrophage inflammatory protein),活化了CFU-EC表面之MIP-3alpha專一接受器CCR6 (C-C chemokine receptor 6),引起了CFU-EC之趨化移動;相對的,我們轉入ECFC誘發表現MIP-3alpha專一接受器CCR6,明顯誘導ECFC趨化移動到肝癌細胞株。在發炎活性方面,肝癌細胞株藉由抑制NF-kappa B活性而明顯降低CFU-EC與ECFC表現出表面發炎分子ICAM1、VCAM1、E-selectin。除此之外,我們進一步探討平滑肌細胞(smooth muscle cells)與內皮細胞(endothelial cells)的共同血管微環境系統(vascular niche)對於血液中流動之原始內皮先驅細胞的移動性(mobility)與分化潛能之影響與相關機制。結果發現CD34+CD31+先驅細胞表現高度的纖維連接蛋白(fibronecitn)貼附性與內皮細胞沾黏性,並移植入活體受損血管內證實此類細胞在新生內膜區(neointima)中會呈現區域分化(compartmental differentiation)生成內皮細胞以及巨噬細胞。共同培養平滑肌細胞會促進CD34+CD31+先驅細胞移動性,包括貼附或移動過(transmigration)於內皮細胞層,而停留於內皮層之貼附CD34+CD31+先驅細胞,特性相似於衍生內皮先驅細胞,具有活體內形成血管新生骨架之細胞能力,移動入平滑肌細胞層之CD34+CD31+先驅細胞會分化成骨髓系內皮先驅細胞CFU-EC,具有功能性巨噬細胞並誘發血管新生能力。進一步證實在內皮細胞與平滑肌細胞組成之微環境下,CD34+CD31+細胞藉由活化beta2 integrin/ICAM-1與Notch1/Jagged-1訊息傳遞調節其移動性與分化潛能,並且beta2 integrin活化後的CD34+CD31+細胞直接移植入受損血管區域,可幫助內皮細胞層之修補(reendothelialization)以及抑制內膜層增生。我們的結果證實血管內皮細胞與平滑肌細胞所組成之血管微環境,可以藉由integrin beta2與Notch1訊息活化去扮演著CD34+CD31+先驅細胞分化路徑的開關,誘導內皮先驅細胞分化與功能性變化。這些結果顯示血管與腫瘤微環境會藉由表現出特定分子或分泌出細胞激素活化細胞間訊息,例如beta2 integrin/ICAM-1與Notch1/Jagged-1與MIP-3alpha/CCR6,調節不同表型之內皮先驅細胞的潛能特性與移動性,而釐清細胞間的分子交互作用,不僅增加我們對動脈硬化或腫瘤血管新生的機制了解,同時也對於未來的心血管或腫瘤疾病,提供新的治療與預防方向。
The count of circulating endothelial progenitor cells (EPCs) is highly related to cardiovascular disease risk and the neovascularization of carcinoma development. However, the implication of these progenitor cells in vasculature is hampered by the incomprehension on their characterization and plasticity mediated by their cellular microenvironment. Three distinct phenotypes of EPCs, i.e., circulating CD34+CD31+ progenitors (circulating EPC), myeloid-derived EPCs (colony forming unit-endothelial cells, CFU-ECs) and outgrowth EPCs (endothelial-colony forming cells, ECFCs) are thought to play different roles in atherosclerotic plaque formation and angiogenesis. The aims of this thesis (1) to investigated whether interactions between EPCs and hepatocarcinoma cells (HCC) affect chemotactic and pro-inflammatory activities of EPCs. (2) to investigated the role of vascular smooth muscle cells (SMCs) and their interactions with endothelial cells (ECs) in the behavior and plasticity of circulating CD34+CD31+ progenitors and its underlying mechanisms. The results showed that the role of HCC in the chemotactic mobility and pro-inflammatory activities of EPCs. To monitor and analyze the migration and invasion of EPCs induced by these HCC cells, CFU-ECs and ECFCs were co-cultured with Huh7 and Hep3B hepatocarcinoma cells by using transwell chamber and novel horizontal migration/invasion assays and time-lapse microscopy. The results show that co-culture with Huh7 and Hep3B cells induces the expression of endothelial cell (EC) markers KDR, Flt1, CD31 and VE-cadherin in CFU-ECs, but down-regulates the expressions of CD31 and VE-cadherin in ECFCs. These HCC cells induce migration and invasion of CFU-ECs, but not ECFCs, and do not affect the cell cycle distribution in these EPCs. Cytokine protein array identifies macrophage inflammatory protein-3 alpha(MIP-3alpha) produced by HCC cells as a critical factor responsible for the HCC-induced chemotaxis of CFU-ECs, which highly express the specific MIP-3alpha counterreceptor CCR6. Overexpressing CCR6 in ECFCs significantly increases their chemotaxis in response to HCC cells. Co-culturing EPCs with HCC cells results in decreases in NF-kappaB binding activity and hence intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expressions in EPCs. In addition, we further studied human peripheral blood CD34+CD31+ progenitors exhibit high fibronectin/EC-adhesiveness. These progenitors injected into wire-injured mouse femoral arteries exhibit compartmental plasticity toward ECs and macrophages in the neo-endothelial layer and neointima, respectively. SMC-co-culture increases CD34+CD31+ cell mobility, adhesion to and transmigration across ECs. Sorted CD34+CD31+ progenitors adhered on ECs co-cultured with SMCs have capacities to form capillary-like structures in Matrigel and chimeric blood vessels when transplanted into immunodeficient mice. In contrast, sorted transmigrated progenitors give rise to functional macrophages, with increased pro-angiogenic activity. This compartmental plasticity of CD34+CD31+ progenitors toward ECs and macrophages is mediated by beta2 integrin and Notch-1, which can be activated by their counterligands intercellular adhesion molecule-1 (ICAM-1) and jagged-1 that are highly expressed in the neoendothelial layer and neointimal SMC-rich region in injured arteries, respectively. Intraarterial injection of beta2-integrin-activated CD34+CD31+ progenitors into wire-injured femoral arteries inhibits neointima formation. Our findings indicate that vascular niches composed of ECs and SMCs may discriminate different CD34+CD31+ progenitor subpopulations to facilitate their compartmental plasticity toward ECs and macrophages through activations of ICAM-1/beta2-integrin and jagged-1/Notch-1 cascades. Take together, vascular niche and tumour microenvironment may modulate the behavior and differentiation potential of different EPC phenotypes through the expression of molecular factors or by creating permissive conditions. The identification of these intercellular signaling cascades could not only provide new insights into the mechanisms of atherosclerosis and tumor development but also aid in the future development of cell therapy and anti-tumor strategies.
TABLE OF CONTENT
中文摘要 1
英文摘要 3
Chapter I. Introduction 5
1.1. Endothelial progenitor cells (EPCs) in peripheral blood mononuclear cells 6
1.2. Contribution of EPCs to the progression of tumor development. 8
1.3. EPCs and the development of atherosclerosis. 10
1.4. Endothelial cells (ECs)-smooth muscle cells (SMCs) interaction in vascular niche 11
1.5. Molecular mechanisms of 2-integrin and Notch signaling cascacde in vascular biology. 12
1.6. The aims of the thesis. 14
Chapter II. Materials and Methods 15
2.1. Materials 16
2.1.1. Cell culture 16
2.1.2. Antibodies and recombinant protein 18
2.1.3. Medium 19
2.1.4. Chemicals and reagents 20
2.1.5. Buffers 20
2.2. Protocols for studying the effect of hepatocellular carcinoma on differentiation and behavior modulation of EPCs 20
2.2.1. Horizontal chemotactic mobility assay 20
2.2.2. Horizontal collagen gel invasion assay 21
2.2.3. Reverse transcription-polymerase chain reaction (RT-PCR) analysis 22
2.2.4. Matrigel pseudotube-formation assay 22
2.2.5. Transwell migration and invasion assays 23
2.2.6. Flow cytometry 24
2.2.7. Electrophoretic mobility shift assay (EMSA) 24
2.2.8. Ectopic full-length CCR6 plasmid transfection 25
2.2.9. Protein array assay 26
2.2.10. Statistical analysis 26
2.3. Protocols for studying the effect of vascular niches on the differentiation and mobility of CD34+CD31+ progenitor cells 27
2.3.1. EC/SMC co-culture models. 27
2.3.2. Animals. 28
2.3.3. Cell mobility assay. 28
2.3.4. Adhesion and transmigration assays. 29
2.3.5. Flow cytometric and cell sorter analysis. 30
2.3.6. RNA isolation and RT-PCR. 31
2.3.7. Immunofluorescence staining. 31
2.3.8. In vitro wound healing assays. 32
2.3.9. Matrigel Pseudo-tube formation assay. 32
2.3.10. Foam cell formation. 33
2.3.11. Femoral artery wire injury model and cell transplantation. 33
2.3.12. Immunohistochemical staining of frozen sections. 34
2.3.13. Morphometric analysis and quantification of lesion formation. 35
2.3.14. Evans blue and Oil Red O staining of the vessel. 35
2.3.15. Matrigel plug implantation assay. 36
2.3.16. Direct in vivo angiogenesis assay (DIVAATM). 36
2.3.17. Statistical analysis. 37
Chapter III. Results 38
3.1. The effect of hepatocellular carcinoma on differentiation and behavior modulation of culture-expanded EPCs 39
3.1.1. Human PBMC-derived EPC subpopulations CFU-ECs and ECFCs exhibit distinct phenotype. 39
3.1.2. Co-culture of EPCs with HCCs results in the altered expression of EC and angiogenic markers in EPC. 40
3.1.3. HCC cells induce chemotaxis of CFU-ECs, but not ECFCs. 40
3.1.4. HCC cells stimulate chemotactic invasion of CFU-ECs, but not ECFCs. 41
3.1.5. Co-culture with HCC cells does not alter the cell cycle distribution in EPCs. 42
3.1.6. The MIP-3/CCR6 signaling axis is critical for HCC-mediated CFU-EC migration and invasion. 42
3.1.7. Overexpressing CCR6 in ECFCs increases their chemotactic activity in response to MIP-3 and Hep3B-co-culture. 44
3.1.8. EPCs in close proximity to HCC cells show reduced expression of pro-inflammatory adhesion molecules via inhibition of NF-B binding activity. 45
3.2. The effect of vascular niches on the differentiation and mobility of CD34+CD31+ progenitor cells 47
3.2.1. CD34CD31 cells express both EC and hematopoietic lineage antigens and exhibit high fibronectin/EC-adhesiveness, with two distinct behaviors when adhering to ECs. 47
3.2.2. Compartmental plasticity of transplanted CD34+CD31+ progenitors toward endothelial and macrophage lineages in the injured arterial wall in vivo. 48
3.2.3. SMCs in close proximity to ECs increase CD34CD31 cell mobility and adhesion to and transmigration across ECs. 48
3.2.4. CD34CD31 progenitors adhered on and transmigrated across ECs co-cultured with SMCs may represent two cell subpopulations, with different plasticity toward ECs and macrophages. 49
3.2.5. CD34+CD31+ progenitors adhered on and transmigrated across ECs co-cultured with SMCs play differential roles in neovascularization and host angiogenesis in vivo. 51
3.2.6. SMCs in close proximity to ECs induce EC ICAM-1 expression and activate 2 integrin on CD34CD31 cells adhered on ECs, and this ICAM-1/2 integrin signaling activation promotes CD34CD31 cell recruitment and endothelial differentiation. 52
3.2.7. Transmigrated CD34CD31 progenitors in EC/SMC co-culture have high levels of Notch-1 activation, which may promote their differentiation into macrophages. 53
3.2.8. Intraarterial injection of 2-integrin-activated CD34+CD31+ progenitors into injured femoral arteries in apoE/ mice inhibits neointima formation. 54
Chapter IV. Discussion 56
4.1. Tumor micro-environment educated the phenotype of CFU-ECs and ECFCs. 57
4.2. The recruitment of CFU-ECs to hepatomacarcinoma specially induced from MIP-3/CCR6 axis. 58
4.3. The distinct mechanism of CFU-ECs and ECFCs contribute to the angiogenesis of hepatocarcinoma. 59
4.4. MIP-3/CCR6 signaling axis is important for the progression of hepatocarcinoma development. 59
4.5. Modulation of pro-inflammatory adhesion molecules on EPCs in close to the hepato-carcinoma micro-environment. 61
4.6. The distinct antigen expression on circulating endothelial progenitors. 62
4.7. Vascular niche mediated the differentiation/mobility of CD34+CD31+ progenitors in the different compartment. 62
4.8. The adherent and transmigrated progenitor derived from CD34+CD31+ progenitor were related to ECFCs and CFU-ECs derived from mononuclear cells. 63
4.9. SMC proximal to EC construct the inflammatory vascular niche expressing ICAM-1 and Jag-1, contribute to the differentiation and mobility of CD34+CD31+ progenitor. 64
4.10. The application of CD34+CD31+ progenitor and ICAM-1-activeated CD34+CD31+ progenitor. 66
Chapter V. Conclusion 68
Chapter VI. Reference 71
Chapter VII. Table and Figures 82
Table 1. Primer sequences and the numbers of reaction cycles used by RT-PCR. 83
Table 2. Quantitative analysis of chemotactic migration paths of CFU-ECs induced by Hep3B cells. 84
Table 3. Paracrine effect of HCC cells on cell cycle distribution in CFU-ECs, ECFCs, and ECs. 85
Table 4. Quantitative analysis of migration paths of CD34CD31 cells in different models 86
Table 5. Cell cycle distribution in the sorted adherent and transmigrated CD34+CD31+ progenitors, as well as CFU-ECs and ECFCs. 87
Figure 1. CFU-ECs and ECFCs exhibit different phenotypes in vitro. 89
Figure 2. Co-culture with HCC cells modulates the expression of EC-lineage markers in CFU-ECs and ECFCs. 92
Figure 3. Co-culture with HCC cells induces migration of ex vivo cultivated CFU-ECs, but not ECFCs. 94
Figure 4. Directional invasion of CFU-ECs induced by co-culture with HCCs. 96
Figure 5. Identification of MIP-3 produced by HCC cells and expression of its specific counterreceptor CCR6 in CFU-ECs. 98
Figure 6. MIP-3 released from HCC cells modulates co-culture-induced motility of CFU-ECs. 101
Figure 7. ECFCs overexpressing CCR6 exhibit chemotactic activity in response to HCC cells and MIP-3. 103
Figure 8. Co-culture with HCC cells results in inhibitions in pro-inflammatory adhesion molecule expression and NF-B binding activity in EPCs. 105
Figure 9. Morphological changes of CD34+-derived progenitor cells cultured on fibronectin-coated dishes. 107
Figure 10. Characterization of HPB CD34+ cells and their CD34CD31 and CD34CD31 cell subpopulations. 109
Figure 11. In vivo differentiation of transplanted CD34+CD31+ progenitors in the injured arterial wall. 112
Figure 12. SMCs induce mobility of CD34CD31 progenitors and their adhesion to and transmigration across ECs. 115
Figure 13. Compartmental differentiation of CD34CD31 progenitors into ECs and macrophages. 120
Figure 14. The phenotype and clonogenic potential analysis of CD34+CD31+-dervied adherent and transmigrated progeny in EC/SMC co-culture. 122
Figure 15. Distributions of the sorted adherent and transmigrated CD34+CD31+ progenitors added onto the scratch-wounded EC monolayer. 124
Figure 17. ICAM-1/2 integrin signaling regulates SMC-induced adhesion and transmigration of CD34CD31 progenitors and their EC-differentiation. 130
Figure 18. Adhesion of CD34+CD31+ progenitors to ICAM-1-Fc- and Dll-4-Fc-coated dishes induces activations of 2 integrin and Notch-1. 133
Figure 19. Transmigrated CD34CD31 progenitors in EC/SMC co-culture have high levels of Notch-1 activation, which promotes their differentiation into macrophages. 137
Figure 20. Intraarterial injection of 2-integrin-activated CD34+CD31+ progenitors into injured femoral arteries in apoE/ mice inhibits neointima formation. 139
Chapter VIII. Publications 140
Chapter IX. Appendix 142


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