血管平滑肌细胞和内皮细胞在小鼠血管损伤模型中的分子机制研究
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摘要
第一章:血管平滑肌细胞系谱追踪
目的:血管平滑肌细胞是构成血管壁组织结构及维持血管张力的主要细胞成分,其结构及功能的改变是导致高血压、动脉粥样硬化和血管成形术后再狭窄等多种心血管病的细胞病理学基础。运用转基因小鼠股动脉的损伤模型模拟临床的血管内膜损伤,通过谱系追踪血管平滑肌细胞的增生、迁移和功能变化来探讨血管损伤后血管重构的病理机制。
方法:运用可诱导的平滑肌细胞特异性标记的转基因小鼠SM22Cre与带有报告基因YFP(黄色荧光蛋白)的小鼠杂交,繁殖出可在诱导剂Tamoxifen注射后,YFP在平滑肌细胞特异表达的转基因小鼠SM22CreYFP。并模拟临床金属支架术,建立小鼠股动脉内膜损伤模型,设立术后0天(未损伤)、术后1天、术后7天、术后14天和21天5个时间点。于各时间点取组织进行免疫化学染色和计数观察。
结果:未损伤时,血管中膜约50%平滑肌细胞被诱导激活,即表达黄色荧光蛋白(YFP),损伤21天后,血管中膜YFP的表达率降为10%,而新生内膜则出现50%YFP表达阳性的平滑肌细胞。
结论在血管损伤后血管发生了重构,新生内膜的平滑肌细胞来源于中膜的平滑肌细胞。有少数新生内膜细胞来源于外膜的CD146阳新细胞。
第二章:血管内皮细胞系谱追踪
目的:内皮细胞作为构成的血管内膜的主要细胞,对于血管损伤后它们的形态学、体外培养和扩增,以及与平滑肌细胞之间相互关系的研究具有重要的意义。运用转基因小鼠颈静脉-股动脉移植模型模拟临床的冠脉大隐静脉搭桥术后血管损伤,通过谱系追踪血管损伤后血管重构,血管内皮细胞的增生和分化病理机制。
方法:运用可诱导的内皮细胞特异性标记的转基因小鼠Tie2Cre与带有报告基因YFP(黄色荧光蛋白)的小鼠杂交,繁殖出可在诱导剂Tamoxifen注射后,YFP在平滑肌细胞特异表达的转基因小鼠Tie2CreYFP。并模拟临床静脉移植术,建立小鼠颈静脉-股动脉内膜损伤模型,设立术后0天(未损伤)、术后3天、术后7天、术后14天和35天5个时间点。于各时间点取组织进行免疫化学染色和计数观察。
结果:活体的静脉移植实验中,标记YFP的内皮细胞系细胞逐渐获得平滑肌细胞的特征,而失去内皮细胞的特征。在离体实验中,EOMA细胞(小鼠内皮细胞瘤)在转化生长因子(TGF-β1)诱导4天后同样显示出平滑肌细胞的特性而失去原有的内皮细胞特征。
结论:在血管移植后移植血管发生了血管重构,增厚的新生内膜中的内皮细胞转化为平滑肌样细胞,TGF-β1在内皮间质化(EMT)中起到了主导作用。
第三章:周期素依赖性蛋白激酶抑制因子在血管内膜增生中的作用
目的:p21~(Cip1)作为周期素依赖性蛋白激酶抑制剂之一,不仅在生理条件下与正常的细胞再生周期有关,而且在病理条件下的血管重构中也扮演着积极的角色。探讨在血管损伤模型中,敲除基因p21~(Cip1)纯合子小鼠在血管损伤后是否能加速血管新生内膜平滑肌过度增生。
方法:通过自交杂合子小鼠P21+/-,培育出纯合子基因敲除小鼠P21-/-和P21+/+,建立双侧股动脉的血管损伤模型,设7天和14天两个时间点,并于处死动物的前1天,给予腹腔注射Brdu,各时间点收集组织标本进行免疫组织化学染色,且进行细胞计数和显微镜下观察分析。
结果:在血管损伤后,p21-/-组小鼠较P21+/+组小鼠显示出更显著的增厚新生内膜,经染色后,p21-/-组小鼠Brdu阳性细胞数目明显高于P21+/+组小鼠。
结论:p21~(Cip1)在血管损伤的增生反应中起到了抑制和减轻血管新生内膜形成的作用。
Chapter 1 SM22-alpha VSMC-lineage tracking during vascular remodeling in a femoral artery injury model
Objectives:Vascular smooth muscle cell(VSMC) expansion and Endothelia cell damage are the main feature of vascular wall thickening after an injury during the vascular remodeling.However,SMC depletion at the early stages warrants investigation into the sources of SMCs during vascular remodeling.To determine the fate of vascular smooth muscle cells after vascular injury.
Methods:we generated a transgenic mouse line,SM22Cre mice expressing a tamoxifen-inducible Cre recombinase,which is controlled by the smooth muscle-specific SM22 promoter.SM22Cre mice were crossed with mice carrying the yellow fluorescent protein(YFP) controlled by the ubiquitous R26R promoter but with a floxed stop codon in between;in effect,tamoxifen injections resulted in YFP expression exclusively in vascular SMCs.We established a femoral artery wire injury model for Sm22aCreYFP mice,and harvested tissues at the following time points:hour 0,day 1,day 7,day 14 and day 21.
Results:In Sm22aCreYFP mice-wire injury model,we found that approximately 50%of vascular SMCs express YFP in the media with a single-layer of endothelial cells in the intima.At day 21,the YFP-expressing cells in the media decreased to around 10%.In contrast, YFP-expressing cells composed approximately 50%of the total neointimal cells.
Conclusion:These findings demonstrate that the medial SMCs contribute to the formation of the neointimal SMCs in vascular remodeling.
Chapter 2 Tie2-endothelial lineage tracking in a murine vein graft model
Objectives:It is very important to study proliferate endothelial cell and smooth muscle cell and mutual relation and morphology during a vascular remodling,for those are essential vascular cells.To determine the fate of endothelial cells after vein graft dring the vascular remodeling.
Methods:we generated a transgenic mouse line,Tire2Cre mice, expressing a tamoxifen-inducible Cre recombinase,which is controlled by the endothelia cell cell-specific Tie2 promoter.Tire2Cre mice were crossed with mice carrying the yellow fluorescent protein(YFP) controlled by the ubiquitous R26R promoter but with a floxed stop codon in between;in effect,tamoxifen injections resulted in YFP expression exclusively in vascular endothelial cells.We established a Jugular vein graft to femoral artery model for Tie2creYFP mice,and harvested tissues at the following time points:hour 0,day3 day,day 7,day 14 and day 35.
Results:In Tie2CreYFP mice-Jugular vein graft model,we found that Endothelial-lineage cells lose endothelial markers and gain SMC characteristics as they proliferate in the neointima in vivo.The endothelial cells(eoma cells) which were treated with TGFβ1 for 4 days gain SMC characteristics in vitro.
Conclusion:These findings demonstrate that Endothelial-lineage cells contribute to the formation of the neointimal SMCs in vascular remodeling.
Chapter 3 cyclin dependent kinase inhibitors play a important role in vascular injury
Objectives:p21~(Cip1),one of the cyclin dependent kinase inhibitors,is implicated in physiologic cell turnover during normal regenerative cycles, as well as being active players in vascular remodeling.To determine lesion formation in mice with homozygous deletion of p21~(Cip1) resulted in accelerated proliferation of vascular smooth muscle cells.
Methods:We established a wire injury model for p21-/- mice and wild type mice,and harvested tissues at the following time points:day7 and day 14.
Results:The p21-/- mice increase neointima formation compare to WT mice indicates that p21~(Cip1) plays a important role in restraining excessive proliferation during vascular wound repair in local vascular cells.The deletion of p21~(Cip1) increased apoptosis in vascular cells,which suggests that p21~(Cip1) plays a role in the control of both proliferation and cell death.
Conclusion:These findings demonstrate that p21~(Cip1) activity in local vascular cells is essential for regulation of both cell proliferation and death in response to vascular injury,and it is a key mediator of vascular proliferation in response to injury.
目的:血管平滑肌细胞是构成血管壁组织结构及维持血管张力的主要细胞成分,其结构及功能的改变是导致高血压、动脉粥样硬化和血管成形术后再狭窄等多种心血管病的细胞病理学基础。运用转基因小鼠股动脉的损伤模型模拟临床的血管内膜损伤,通过谱系追踪血管平滑肌细胞的增生、迁移和功能变化来探讨血管损伤后血管重构的病理机制。
方法:运用可诱导的平滑肌细胞特异性标记的转基因小鼠SM22Cre与带有报告基因YFP(黄色荧光蛋白)的小鼠杂交,繁殖出可在诱导剂Tamoxifen注射后,YFP在平滑肌细胞特异表达的转基因小鼠SM22CreYFP。并模拟临床金属支架术,建立小鼠股动脉内膜损伤模型,设立术后0天(未损伤)、术后1天、术后7天、术后14天和21天5个时间点。于各时间点取组织进行免疫化学染色和计数观察。
结果:未损伤时,血管中膜约50%平滑肌细胞被诱导激活,即表达黄色荧光蛋白(YFP),损伤21天后,血管中膜YFP的表达率降为10%,而新生内膜则出现50%YFP表达阳性的平滑肌细胞。
结论在血管损伤后血管发生了重构,新生内膜的平滑肌细胞来源于中膜的平滑肌细胞。有少数新生内膜细胞来源于外膜的CD146阳新细胞。
第二章:血管内皮细胞系谱追踪
目的:内皮细胞作为构成的血管内膜的主要细胞,对于血管损伤后它们的形态学、体外培养和扩增,以及与平滑肌细胞之间相互关系的研究具有重要的意义。运用转基因小鼠颈静脉-股动脉移植模型模拟临床的冠脉大隐静脉搭桥术后血管损伤,通过谱系追踪血管损伤后血管重构,血管内皮细胞的增生和分化病理机制。
方法:运用可诱导的内皮细胞特异性标记的转基因小鼠Tie2Cre与带有报告基因YFP(黄色荧光蛋白)的小鼠杂交,繁殖出可在诱导剂Tamoxifen注射后,YFP在平滑肌细胞特异表达的转基因小鼠Tie2CreYFP。并模拟临床静脉移植术,建立小鼠颈静脉-股动脉内膜损伤模型,设立术后0天(未损伤)、术后3天、术后7天、术后14天和35天5个时间点。于各时间点取组织进行免疫化学染色和计数观察。
结果:活体的静脉移植实验中,标记YFP的内皮细胞系细胞逐渐获得平滑肌细胞的特征,而失去内皮细胞的特征。在离体实验中,EOMA细胞(小鼠内皮细胞瘤)在转化生长因子(TGF-β1)诱导4天后同样显示出平滑肌细胞的特性而失去原有的内皮细胞特征。
结论:在血管移植后移植血管发生了血管重构,增厚的新生内膜中的内皮细胞转化为平滑肌样细胞,TGF-β1在内皮间质化(EMT)中起到了主导作用。
第三章:周期素依赖性蛋白激酶抑制因子在血管内膜增生中的作用
目的:p21~(Cip1)作为周期素依赖性蛋白激酶抑制剂之一,不仅在生理条件下与正常的细胞再生周期有关,而且在病理条件下的血管重构中也扮演着积极的角色。探讨在血管损伤模型中,敲除基因p21~(Cip1)纯合子小鼠在血管损伤后是否能加速血管新生内膜平滑肌过度增生。
方法:通过自交杂合子小鼠P21+/-,培育出纯合子基因敲除小鼠P21-/-和P21+/+,建立双侧股动脉的血管损伤模型,设7天和14天两个时间点,并于处死动物的前1天,给予腹腔注射Brdu,各时间点收集组织标本进行免疫组织化学染色,且进行细胞计数和显微镜下观察分析。
结果:在血管损伤后,p21-/-组小鼠较P21+/+组小鼠显示出更显著的增厚新生内膜,经染色后,p21-/-组小鼠Brdu阳性细胞数目明显高于P21+/+组小鼠。
结论:p21~(Cip1)在血管损伤的增生反应中起到了抑制和减轻血管新生内膜形成的作用。
Chapter 1 SM22-alpha VSMC-lineage tracking during vascular remodeling in a femoral artery injury model
Objectives:Vascular smooth muscle cell(VSMC) expansion and Endothelia cell damage are the main feature of vascular wall thickening after an injury during the vascular remodeling.However,SMC depletion at the early stages warrants investigation into the sources of SMCs during vascular remodeling.To determine the fate of vascular smooth muscle cells after vascular injury.
Methods:we generated a transgenic mouse line,SM22Cre mice expressing a tamoxifen-inducible Cre recombinase,which is controlled by the smooth muscle-specific SM22 promoter.SM22Cre mice were crossed with mice carrying the yellow fluorescent protein(YFP) controlled by the ubiquitous R26R promoter but with a floxed stop codon in between;in effect,tamoxifen injections resulted in YFP expression exclusively in vascular SMCs.We established a femoral artery wire injury model for Sm22aCreYFP mice,and harvested tissues at the following time points:hour 0,day 1,day 7,day 14 and day 21.
Results:In Sm22aCreYFP mice-wire injury model,we found that approximately 50%of vascular SMCs express YFP in the media with a single-layer of endothelial cells in the intima.At day 21,the YFP-expressing cells in the media decreased to around 10%.In contrast, YFP-expressing cells composed approximately 50%of the total neointimal cells.
Conclusion:These findings demonstrate that the medial SMCs contribute to the formation of the neointimal SMCs in vascular remodeling.
Chapter 2 Tie2-endothelial lineage tracking in a murine vein graft model
Objectives:It is very important to study proliferate endothelial cell and smooth muscle cell and mutual relation and morphology during a vascular remodling,for those are essential vascular cells.To determine the fate of endothelial cells after vein graft dring the vascular remodeling.
Methods:we generated a transgenic mouse line,Tire2Cre mice, expressing a tamoxifen-inducible Cre recombinase,which is controlled by the endothelia cell cell-specific Tie2 promoter.Tire2Cre mice were crossed with mice carrying the yellow fluorescent protein(YFP) controlled by the ubiquitous R26R promoter but with a floxed stop codon in between;in effect,tamoxifen injections resulted in YFP expression exclusively in vascular endothelial cells.We established a Jugular vein graft to femoral artery model for Tie2creYFP mice,and harvested tissues at the following time points:hour 0,day3 day,day 7,day 14 and day 35.
Results:In Tie2CreYFP mice-Jugular vein graft model,we found that Endothelial-lineage cells lose endothelial markers and gain SMC characteristics as they proliferate in the neointima in vivo.The endothelial cells(eoma cells) which were treated with TGFβ1 for 4 days gain SMC characteristics in vitro.
Conclusion:These findings demonstrate that Endothelial-lineage cells contribute to the formation of the neointimal SMCs in vascular remodeling.
Chapter 3 cyclin dependent kinase inhibitors play a important role in vascular injury
Objectives:p21~(Cip1),one of the cyclin dependent kinase inhibitors,is implicated in physiologic cell turnover during normal regenerative cycles, as well as being active players in vascular remodeling.To determine lesion formation in mice with homozygous deletion of p21~(Cip1) resulted in accelerated proliferation of vascular smooth muscle cells.
Methods:We established a wire injury model for p21-/- mice and wild type mice,and harvested tissues at the following time points:day7 and day 14.
Results:The p21-/- mice increase neointima formation compare to WT mice indicates that p21~(Cip1) plays a important role in restraining excessive proliferation during vascular wound repair in local vascular cells.The deletion of p21~(Cip1) increased apoptosis in vascular cells,which suggests that p21~(Cip1) plays a role in the control of both proliferation and cell death.
Conclusion:These findings demonstrate that p21~(Cip1) activity in local vascular cells is essential for regulation of both cell proliferation and death in response to vascular injury,and it is a key mediator of vascular proliferation in response to injury.
引文
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[5] Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med2002; 8: 403-9.
[6] Liu C, Nath KA, Katusic ZS, Caplice NM. Smooth muscle progenitor cells in vascular disease. Trends Cardiovasc Med 2004; 14: 288-93.
[7] Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med 2001; 7: 382-3.
[8] Shimizu K, Sugiyama S, Aikawa M, et al. Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy.Nat Med 2001; 7: 738-41.
[9] Hu Y, Mayr M, Metzler B, et al. Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res 2002; 91: el3-20.
[10] Grimm PC, Nickerson P, Jeffery J, et al. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N Engl J Med 2001; 345: 93-7.
[1 l]Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Engl J Med 2002; 346: 5-15.
[12]Kirby ML, Waldo KL. Role of neural crest in congenital heart disease.Circulation 1990; 82: 332-40.
[13]Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest:analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol 1975; 34: [14] 125-54.
[15]Majka SM, Jackson KA, Kienstra KA, et al. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration. J Clin Invest 2003; 111:71-9.
[16]Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114: 763-76.
[17]Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701-5.
[18]Hillebrands J, van den Hurk BM, Klatter FA, et al. Recipient origin of neointimal vascular smooth muscle cells in cardiac allografts with transplant arteriosclerosis. J Heart Lung Transplant 2000; 19:1183-92.
[19]Hu Y, Zhang Z, Torsney E, et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 2004;113:1258-65.
[20] Li G, Chen SJ, Oparil S, Chen YF, Thompson JA. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation 2000; 101: 1362-5.
[21]Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997; 277: 242-5.
[22] Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM. Smooth muscle progenitor cells in human blood. Circulation 2002; 106: 1199-204.
[23]Yamashita J, Itoh H, Hirashima M, et al. Flkl-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 2000; 408: 92-6.
[24] Arciniegas E, Sutton AB, Allen TD, Schor AM. Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells in vitro. J Cell Sci 1992; 103 (Pt 2): 521-9.
[25] Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res 2002; 90: 1189-96.
[26] Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542-5.
[27]Wurmser AE, Gage FH. Stem cells: cell fusion causes confusion. Nature 2002;416: 485-7.
[28] Barrett TB, Sampson P, Owens GK, Schwartz SM, Benditt EP. Polyploid nuclei
[29]in human artery wall smooth muscle cells.Proc Natl Acad Sci U S A 1983;80:882-5.
[30]Murry CE,Soonpaa MH,Reinecke H,et al.Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts.Nature 2004;428:664-8.
[31]Balsam LB,Wagers AJ,Christensen JL,et al.Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.Nature 2004;428:668-73.
[32]Erl W.Statin-induced vascular smooth muscle cell apoptosis:a possible role in the prevention of restenosis? Curr Drug Targets Cardiovasc Haematol Disord 2005;5:135-44.
[33]Asahara T,Murohara T,Sullivan A,et al.Isolation of putative progenitor endothelial cells for angiogenesis.Science 1997;275:964-7.
[34]Mathur A,Martin JF.Stem cells and repair of the heart.Lancet 2004;364:183-92.
[1]Akhurst R.TGF-b signaling in epithelial-mesenchymal transition and invasion and metastasis.In:Derynck R,Miyazono K,eds.The TGF-beta family.Cold Spring Harbor Laboratory Press:New York 2007:939-964.
[2]Tsukita S,Furuse M,Itoh M.Multifunctional strands in tight junctions.Nat Rev Mol Cell Biol 2001;2:285-293.
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[4]Martin-Belmonte F,Mostov K.Regulation of cell polarity during epithelial morphogenesis.Curr Opin Cell Biol 2008;20:227-234.
[5]Niessen CM,Gottardi CJ.Molecular components of the adherens junction.Biochim Biophys Acta 2008;1778:562-571.
[6]Wheelock MJ,Johnson KR.Cadherins as modulators of cellular phenotype.Annu Rev Cell Dev Biol 2003;19:207-235.
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[8]Navarro P,Lozano E,Cano A.Expression of E-or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells.Possible involvement of plakoglobin.J Cell Sci 1993;105:923-934.
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[10] plays an essential role in tumor metastasis.Cell 2004; 117:927-939.
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[12] De Craene B, Gilbert B, Stove C, et al. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res 2005;65:6237-6244.
[13] Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of Ecadherin downregulation. J Cell Sci2004; 117:1675-1685.
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[16] Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000;2:76-83.
[17] Savagner P, Yamada KM, Thiery JP. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition.J Cell Biol 1997; 137:1403-1419.
[18] Miettinen PJ, Ebner R, Lopez AR, Derynck R. TGF-binduced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J CellBiol 1994; 127:2021-2036.
[19] Imamichi Y, Menke A. Signaling pathways involved in collagen-induced disruption of the E-cadherin complex during epithelial-mesenchymal transition. Cells Tissues Organs2007; 185:180-190.
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[1] Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.
[2] Zohlnhofer D, Klein CA, Richter T, et al. Gene expression profiling of human stent-induced neointima by cDNA array analysis of microscopic specimens retrieved by helix cutter atherectomy: Detection of FK506-binding protein 12 upregulation. Circulation 2001; 103: 1396-402.
[3] Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science1996; 273:242-5.
[4] Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276: 71-4.
[5] Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med2002; 8: 403-9.
[6] Liu C, Nath KA, Katusic ZS, Caplice NM. Smooth muscle progenitor cells in vascular disease. Trends Cardiovasc Med 2004; 14: 288-93.
[7] Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med 2001; 7: 382-3.
[8] Shimizu K, Sugiyama S, Aikawa M, et al. Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy.Nat Med 2001; 7: 738-41.
[9] Hu Y, Mayr M, Metzler B, et al. Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res 2002; 91: el3-20.
[10] Grimm PC, Nickerson P, Jeffery J, et al. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N Engl J Med 2001; 345: 93-7.
[1 l]Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Engl J Med 2002; 346: 5-15.
[12]Kirby ML, Waldo KL. Role of neural crest in congenital heart disease.Circulation 1990; 82: 332-40.
[13]Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest:analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol 1975; 34: [14] 125-54.
[15]Majka SM, Jackson KA, Kienstra KA, et al. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration. J Clin Invest 2003; 111:71-9.
[16]Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114: 763-76.
[17]Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701-5.
[18]Hillebrands J, van den Hurk BM, Klatter FA, et al. Recipient origin of neointimal vascular smooth muscle cells in cardiac allografts with transplant arteriosclerosis. J Heart Lung Transplant 2000; 19:1183-92.
[19]Hu Y, Zhang Z, Torsney E, et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 2004;113:1258-65.
[20] Li G, Chen SJ, Oparil S, Chen YF, Thompson JA. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation 2000; 101: 1362-5.
[21]Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997; 277: 242-5.
[22] Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM. Smooth muscle progenitor cells in human blood. Circulation 2002; 106: 1199-204.
[23]Yamashita J, Itoh H, Hirashima M, et al. Flkl-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 2000; 408: 92-6.
[24] Arciniegas E, Sutton AB, Allen TD, Schor AM. Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells in vitro. J Cell Sci 1992; 103 (Pt 2): 521-9.
[25] Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res 2002; 90: 1189-96.
[26] Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542-5.
[27]Wurmser AE, Gage FH. Stem cells: cell fusion causes confusion. Nature 2002;416: 485-7.
[28] Barrett TB, Sampson P, Owens GK, Schwartz SM, Benditt EP. Polyploid nuclei
[29]in human artery wall smooth muscle cells.Proc Natl Acad Sci U S A 1983;80:882-5.
[30]Murry CE,Soonpaa MH,Reinecke H,et al.Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts.Nature 2004;428:664-8.
[31]Balsam LB,Wagers AJ,Christensen JL,et al.Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.Nature 2004;428:668-73.
[32]Erl W.Statin-induced vascular smooth muscle cell apoptosis:a possible role in the prevention of restenosis? Curr Drug Targets Cardiovasc Haematol Disord 2005;5:135-44.
[33]Asahara T,Murohara T,Sullivan A,et al.Isolation of putative progenitor endothelial cells for angiogenesis.Science 1997;275:964-7.
[34]Mathur A,Martin JF.Stem cells and repair of the heart.Lancet 2004;364:183-92.
[1]Akhurst R.TGF-b signaling in epithelial-mesenchymal transition and invasion and metastasis.In:Derynck R,Miyazono K,eds.The TGF-beta family.Cold Spring Harbor Laboratory Press:New York 2007:939-964.
[2]Tsukita S,Furuse M,Itoh M.Multifunctional strands in tight junctions.Nat Rev Mol Cell Biol 2001;2:285-293.
[3]Assemat E,Bazellieres E,Pallesi-Pocachard E,Le Bivic A,Massey-Harroche D.Polarity complex proteins.Biochim Biophys Acta 2008;1778:614-630.
[4]Martin-Belmonte F,Mostov K.Regulation of cell polarity during epithelial morphogenesis.Curr Opin Cell Biol 2008;20:227-234.
[5]Niessen CM,Gottardi CJ.Molecular components of the adherens junction.Biochim Biophys Acta 2008;1778:562-571.
[6]Wheelock MJ,Johnson KR.Cadherins as modulators of cellular phenotype.Annu Rev Cell Dev Biol 2003;19:207-235.
[7]Llorens A,Rodrigo I,Lopez-Barcons L,et al.Down-regulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype linked to matrix metalloproteinase- gelatinase expression.Lab Invest 1998;78:1131-1142.
[8]Navarro P,Lozano E,Cano A.Expression of E-or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells.Possible involvement of plakoglobin.J Cell Sci 1993;105:923-934.
[9]Yang J,Mani SA,Donaher JL,et al.Twist,a master regulator of morphogenesis,
[10] plays an essential role in tumor metastasis.Cell 2004; 117:927-939.
[11] Ansieau S, Bastid J, Doreau A, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 2008; 14:79-89.
[12] De Craene B, Gilbert B, Stove C, et al. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res 2005;65:6237-6244.
[13] Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of Ecadherin downregulation. J Cell Sci2004; 117:1675-1685.
[14] Garrod D, Chidgey M. Desmosome structure, composition and function.Biochim Biophys Acta 2008; 1778:572-587.
[15] Yin T, Green KJ. Regulation of desmosome assembly and adhesion. Semin Cell DevBiol 2004; 15:665-677.
[16] Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000;2:76-83.
[17] Savagner P, Yamada KM, Thiery JP. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition.J Cell Biol 1997; 137:1403-1419.
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