单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Endothelial Progenitor Cells,Characterization and Role in Vascular Biology,Definition,They are circulating,bone marrow-derived cells that are functionally and phenotypically distinct from mature endothelial cells,They can differentiate into endothelial cells,in vitro,as assessed by expression profiles and functional characteristics,They can contribute to,in vivo,vasculogenesis and/or vascular homeostasis,Endothelial progenitor cell,内皮祖细胞是能直接分化为血管内皮细胞的前体细胞,Embryonic,EPC,胚外中胚层卵黄囊血岛,与造血干细胞存在共同的前体,Adult EPC,Bone Marrow,(,3,%BM-MNC),Peripheral Blood,(,0.2,%MNC),Origin and differentiation of endothelial progenitor cells,Hematopoietic stem cells,CD133+,CD34+,CD45,CD14+,CD45+,CD45+,CD14+,CD45+,CD14+,CD133+,KDR+,CD34+,CD14+,CD133+,Endothelial markers+,Endothelial markers+,EPCs,EPCs,Myeloid Precursor,Monocytes,Macrophage,EPCs,myeloid subtype,Mature EC,?,?,?,?,CD14,low,CD34,low,CD133-,Endothelial markers+,Mesenchymal stem cells,C-kit-,CD34-,Tissue-resident stem cells,C-kit+,EPCs Development,Molecular Mechanisms,Transcription factor SCL/Tal,是参与原血干细胞分化的基本的转录因子。,A basic helix-loop-helix transcription factor,小鼠,SCL,基因无效突变的纯合子引起死亡,表现为卵黄囊毛细血管内皮形成障碍、,早期造血不能发育,VEGFR and VEGF,Receptor,VEGFR-1(flt-1),VEGFR-2(flk-1/KDR),VEGFR-3(flt-4),Ligand,VEGF,、,VEGF-B,C,D,E,EPCs Development,VEGFR and VEGF,研究显示,VEGFR2,缺陷鼠在,E8.5,E9.5,时因缺乏,内皮和造血细胞而死亡,。,Flk1,-/-,的胚胎干细胞离体不能分化为,EPC,。,胚胎干细胞向内皮细胞分化对,VEGF,呈剂量依赖性，,VEGF,浓度增加可增加原血干细胞向,EPC,转化，而,相应减少造血干细胞的生成。,VEGFR1,纯合突变鼠也因内皮细胞不能形成管样结,构而使胚胎在,E9.5,E10,死亡。,VEGF,是唯一已知的在胚胎杂合子状态致死的常染色体基因。,Tie receptor and ligand,：受体酪氨酸激酶家族,receptor,Tie-1(Tie),Tie-2(Tek),Tie-2 ligand,：,Angiopoietin(Ang,，,血管生成素,),Ang-1,：血管内皮化,Ang-2,：血管周围细胞和内皮细胞分离,EPCs Development,Tie receptor and ligand,：受体酪氨酸激酶家族,Tie-2,缺陷的胚胎不能建立血管结构的完整性,Ang-1,缺陷鼠也表现为血管生成缺陷,EPCs Development,Ephs family,Erythropoietin producing hepatocyte receptor(Eph),Ligand:ephrins(Eph A,、,B),Eph B,可调节,Ang-1,和,Tie-2,的表达,EPCs Development,促红细胞生成素肝细胞受体及其配体，是酪氨酸激酶家族中的最大成员。,基因缺失及体外血管形成实验表明：,EphB,和,ephrinB,在胚胎血管分化及成人病理性血管形成中发挥重要作用。,CD34,+,Flk-1,+,CD34,+,Flk-1,+,AC133,+,CD34,+,CD34,+,Flk-1,+,AC133,-,Stem cell,EPC,HSC,EPC,EC,HSC,Circulating,EPC,EC,EPC,EC,CD34-selected culture-dish non-adherent putative EPC(CDNAC)change to a more mature endothelial phenotype during differentiation while the progenitor phenotype remains stable and the monocytic phenotype decreases.,CD34-selected putative EPC from culture-dish adherent cells(CDAC)express lower levels of endothelial and progenitor markers than CDNAC.,VEGFR-2/Flk-1,+,CD31,+,/Tie-2,+,VE-Cadeherin,+,/Tie-1,+,AC133,+,AC133,-,CD34,+,/,VEGFR-2,+,cells can behave as EPCs.,CD133,+,/,CD34,+,/,VEGFR-2,+,cells represent a more primitive EPC.,Putative EPCs take up acetylated low density lipoprotein(,Ac-LDL,)and bind the endothelial specific lectin,UEA-1,.,Mobilization of EPCs,Determined by local microenvironment,(stem cell niche),Fibroblasts,Osteoblasts,Endothelial cells,Stromal cells,Mobilization of EPCs,Stromal cells,Stem cells,Mobilizing cytokines,VEGF,SDF-1,G-CSF,EPO,Statins,estrogen,exercise,hamper,Transendothelial migration,Elastase,Cathepsin,MMPs,Blood circulating,Chemotaxis,Migration and Invasion,SDF-1,VEGF,Adhesion,Integrin,Selectin,Differentiation,VEGF,SDF-1:stromal cell-derived factor-1,EPCs were originally thought to be present,only during embryonic development.,Evidence accumulating over several years,suggests that they can persist in adult life.,This has generated interest in the use of,EPC,s for neovascularization of ischemic or,injured tissue and for the clinical,assessment of risk factors for various,diseases.,EPC,Tumor angiogenesis,Ischemic vasculogenesis/,Wound healing,Vascular homeostasis,EPCsfunction,Embryo vascular network expand,Revascularization,Angiogenesis,Vasculogenesis,Blood vessel development,血管,发生,/,生成,血管,生成,/,新生,/,增生,不但是正常生理变化中,(,如生长、伤口愈合,),所必需有的过程，和肿瘤的发展也有密切的关系。,Angiogenesis,a regulated process involving the proliferation,and migration of endothelial cells from adjacent pre-existing blood vessels.,血管生成,指由已经存在的血管,成熟内皮细胞,通过局部芽生或套叠的形式生成新的毛细血管，是血管,从少到多,的过程，是血管新生的,经典理论,。,Vasculogenesis,a regulated process following differentiation of endothelial progenitor cells from mesodermal precursors/endothelial progenitor cells(EPCs),血管发生,这种方式最早发生在胚胎期的血管生成，直接由,EPCs,或更早来源的血管母细胞,（,angioblast,）,长成，是血管,从无到有,的过程。最近证据表明，,EPCs,参与的血管发生亦参与了出生后机体局部缺血组织的修复。,Vasculo,genesis,和,Angio,genesis,是血管发育过程中的两个阶段，但在中文翻译时出现了意思重叠和相近、不便于区别的问题。,传 统,Angiogenesis,主要是,EC,迁移增殖参与的，,vasculogenesis,在胚胎期和生后均存在，主要依靠,EPC,分化增殖参与。,现 在,1997,年，,Angiogenesis,概念被打破，,Asahara,等证实除有,EC,迁移增殖参与，还有,EPC,的参与。,Decrease of endothelial progenitor cells in the blood is a risk factor for vascular disease.,Depletion or senescence of endothelial progenitor cells may contribute to blood vessel disease.,Endothelial progenitor cell,EPCs and endothelial regeneration,In the past,endothelial regeneration has been attributed to the migration and proliferation of neighboring EC,In 1997,Asahara first demonstrated EPC contributed to endothelial regeneration,