内皮克隆形成细胞的研究进展和应用前景
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摘要
内皮克隆形成细胞(endothelial colony-forming cells, ECFCs)是内皮祖细胞(endothelial progenitor cells, EPCs)的一种亚型,具有高度增殖、克隆形成和裸鼠体内血管形成的能力,在维持血管稳态方面发挥着重要作用。ECFCs的来源很广,包括外周血、脐血、骨髓、血管壁,以及人诱导的多功能干细胞(human-induced pluripotent stem cells, hiPSCs),其中研究较为深入的是外周血ECFCs(PB-ECFCs)和脐血ECFCs(CB-ECFCs)。在此,我们将简要介绍ECFCs功能障碍与疾病的相关性,总结ECFCs在缺血损伤、组织工程以及肿瘤治疗领域的基础研究进展和应用前景,最后对小鼠体内研究的局限性以及细胞体外培养条件改良等问题进行探讨。
Endothelial colony-forming cells(ECFCs), a subtype of endothelial progenitor cells(EPCs), play an important role in maintaining vascular homeostasis. ECFCs are characterized by robust proliferative potential, colony forming ability and ability to form intrinsic in vivo vessels upon transplantation into immunodeficient mice. They have been successfully isolated from the peripheral blood(PB-ECFCs), umbilical cord blood(CB-ECFCs), bone marrow and wall of numerous arterial and venous vessels, and derived from human-induced pluripotent stem cells(hiPSCs). Here we will briefly describe the involvement of ECFCs in various diseases, summarize the current progress and application prospect of CB-ECFCs in ischemia repair, tissue engineering and tumor therapy, and highlight the limitations of in vivo studies in mice and the improvement of cell culture conditions in vitro.
Endothelial colony-forming cells(ECFCs), a subtype of endothelial progenitor cells(EPCs), play an important role in maintaining vascular homeostasis. ECFCs are characterized by robust proliferative potential, colony forming ability and ability to form intrinsic in vivo vessels upon transplantation into immunodeficient mice. They have been successfully isolated from the peripheral blood(PB-ECFCs), umbilical cord blood(CB-ECFCs), bone marrow and wall of numerous arterial and venous vessels, and derived from human-induced pluripotent stem cells(hiPSCs). Here we will briefly describe the involvement of ECFCs in various diseases, summarize the current progress and application prospect of CB-ECFCs in ischemia repair, tissue engineering and tumor therapy, and highlight the limitations of in vivo studies in mice and the improvement of cell culture conditions in vitro.
引文
[1]Bertagnolli M,Xie L F,Paquette K,et al.Endothelial Colony-Forming Cells in Young Adults Born Preterm:A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease[J].J Am Heart Assoc,2018,7(14):e009720
[2]Hernandez-Lopez R,Chavez-Gonzalez A,Torres-Barrera P,et al.Reduced proliferation of endothelial colony-forming cells in unprovoked venous thromboembolic disease as a consequence of endothelial dysfunction[J].PLoS One,2017,12(9):e0183827
[3]Edwards N,Langford-Smith A W W,Wilkinson F L,et al.Endothelial Progenitor Cells:New Targets for Therapeutics for Inflammatory Conditions With High Cardiovascular Risk[J].Front Med(Lausanne),2018,5:200
[4]Lee Jy M Y,Lee Ho,Park Ak,et al.Deregulation of Retinaldehyde Dehydrogenase 2 Leads to Defective Angiogenic Function of Endothelial Colony Forming Cells in Pediatric Moyamoya Disease[J].Arterioscler Thromb Vasc Biol,2015,35(7):1670-1677
[5]Krieter Dh F R,Merget K,Lemke Hd,et al.Endothelial progenitor cells in patients on extracorporeal maintenance dialysis therapy.[J].Nephrol Dial Transplant,2010,25(12):4023-4031
[6]Munoz-Hernandez R,Miranda M L,Stiefel P,et al.Decreased Level of Cord Blood Circulating Endothelial Colony-Forming Cells in Preeclampsia[J].Hypertension,2014,64(1):165-171
[7]Ingram D A,Lien I Z,Mead L E,et al.In vitro hyperglycemia or a diabetic intrauterine environment reduces neonatal endothelial colony-forming cell numbers and function[J].Diabetes,2008,57(3):724-731
[8]Baker C D,Ryan S L,Ingram D A,et al.Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia[J].Am J Respir Crit Care Med,2009,180(5):454-461
[9]Fujinaga H F,Watanabe N,Kato T,et al.Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia[J].Am J Physiol Lung Cell Mol Physiol,2016,310(11):L1143-1154
[10]Peters B A,Diaz L A,Polyak K,et al.Contribution of bone marrowderived endothelial cells to human tumor vasculature[J].Nat Med,2005,11(3):261-262
[11]Mcallister S S,Weinberg R A.The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis[J].Nat Cell Biol,2014,16(8):717-727
[12]Francesco Moccia V F,Richard Tancredi,Matteo Giovanni Della Porta,et al.Breast and renal cancerd Derived endothelial colony forming cells share a common gene signature[J].European Journal of Cancer,2017,77:155-164
[13]Duong Van Huyen Jp S D,Bruneval P,Gaussem P,et al.Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia[J].Mod Pathol,2008,21(7):837-846
[14]Sarlon G,Zemani F,David L,et al.Therapeutic effect of fucoidan-stimulated endothelial colony-forming cells in peripheral ischemia[J].J Thromb Haemost,2012,10(1):38-48
[15]Moubarik C,Guillet B,Youssef B,et al.Transplanted Late Outgrowth Endothelial Progenitor Cells as Cell Therapy Product for Stroke[J].Stem Cell Reviews and Reports,2010,7(1):208-220
[16]Lee S H,Lee J H,Asahara T,et al.Genistein promotes endothelial colony-forming cell(ECFC)bioactivities and cardiac regeneration in myocardial infarction[J].PLo S One,2014,9(5):e96155
[17]Alphonse R S,Vadivel A,Fung M,et al.Existence,functional impairment,and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth[J].Circulation,2014,129(21):2144-2157
[18]Milbauer L C,Enenstein J A,Roney M,et al.Blood outgrowth endothelial cell migration and trapping in vivo:a window into gene therapy[J].Transl Res,2009,153(4):179-189
[19]Kim S-W,Jin H L,Kang S-M,et al.Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair[J].International Journal of Cardiology,2016,203:498-507
[20]Xin-Tao Huang,Y-Q Z,Sheng-Jie Li,et al.Intracerebroventricular Transplantation of ex vivo Expanded Endothelial Colony-Forming Cells Restores Blood Brain Barrier Integrity and Promotes Angiogenesis of Mice with Traumatic Brain Injury[J].J Neurotrauma,2013,30(24):2080-2088
[21]Zemani F,Silvestre J S,Fauvel-Lafeve F,et al.Ex vivo priming of endothelial progenitor cells with SDF-1 before transplantation could increase their proangiogenic potential[J].Arterioscler Thromb Vasc Biol,2008,28(4):644-650
[22]Jun Hee Lee1 S H L,Sung Hyun Choi1,Takayuki Asahar,et al.The Sulfated Polysaccharide Fucoidan Rescues Senescence of Endothelial Colony Forming Cells for Ischemic Repair[J].Stem Cells,2015,33(6):1939-1951
[23]Bennis Y,Sarlon-Bartoli G,Guillet B,et al.Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential[J].J Thromb Haemost,2012,10(9):1914-1928
[24]Sang Hun Lee J H L,Yong-Seok Han,Jung Min Ryu,et al.Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis[J].Stem Cell Research&Therapy,2015,6(1):139
[25]Mena H A,Zubiry P R,Dizier B,et al.Acidic preconditioning of endothelial colony-forming cells(ECFC)promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo[J].Stem Cell Res Ther,2018,9(1):120
[26]Lee S H,Lee K B,Lee J H,et al.Selective Interference Targeting of Lnk in Umbilical Cord-Derived Late Endothelial Progenitor Cells Improves Vascular Repair,Following Hind Limb Ischemic Injury,via Regulation of JAK2/STAT3 Signaling[J].Stem Cells,2015,33(5):1490-500
[27]Falabella Af S L,Valencia Ic,Eaglstein Wh.The use of tissueengineered skin(Apligraf)to treat a newborn with epidermolysis bullosa[J].Arch Dermatol,1999,135(10):1219-1222
[28]Ando W,Tateishi K,Hart D A,et al.Cartilage repair using an in vitro generated scaffold-free tissue-engineered construct derived from porcine synovial mesenchymal stem cells[J].Biomaterials,2007,28(36):5462-5470
[29]Fu J,Wang D A.In Situ Organ-Specific Vascularization in Tissue Engineering[J].Trends Biotechnol,2018,36(8):834-849
[30]Jung H S,Kim M J,Hong S H,et al.The potential of endothelial colony-forming cells to improve early graft loss after intraportal islet transplantation[J].Cell Transplant,2014,23(3):273-783
[31]Traktuev D O,Prater D N,Merfeld-Clauss S,et al.Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells[J].Circ Res,2009,104(12):1410-1420
[32]Goerke Sm O J,Plaha J,Stark Gb,et al.Endothelial progenitor cells from peripheral blood support bone regeneration by provoking an angiogenic response[J].Microvasc Res,2015,98:40-47
[33]Laurenzana A B A,D'alessio S,Bianchini F,et al.Melanoma cell therapy:Endothelial progenitor cells as shuttle of the MMP12uPAR-degrading enzyme[J].Oncotarget,2014,5(11):3711-3727
[34]Margheri G Z A,Olmi R,Trigari S,et al.Tumor-tropic endothelial colony forming cells(ECFCs)loaded with near-infrared sensitive Au nanoparticles:A"cellular stove"approach to the photoablation of melanoma[J].Oncotarget,2016,7(26):39846-39860
[35]Bodempudi V O J,Terai K,Zamora Ea,et al.Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors[J].Cancer Gene Ther,2010,17(12):855-863
[36]Wei J W J,Nakamura T,Stiller D,et al.Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas[J].Gene Ther,2007,14(22):1573-1586
[37]Melero-Martin Jm D O M,Allen P,Dudley Ac,et al.Host Myeloid Cells Are Necessary for Creating Bioengineered Human Vascular Networks in Vivo[J].Tissue Eng Part A,2010,16(8):2457-2466
[38]Naima Souidi M S,Juliane Rudeck,Dirk Strunk,et al.Stromal Cells Act as Guardians for Endothelial Progenitors by Reducing their Immunogenicity after Cotransplantation[J].STEM CELLS,2017,35(5):1233-1245
[39]Burnouf T,Strunk D,Koh M B,et al.Human platelet lysate:Replacing fetal bovine serum as a gold standard for human cell propagation?[J].Biomaterials,2016,76:371-387
[40]Reinisch A H N,Obenauf Ac,Kashofer K,et al.Humanized large-scale expanded endothelial colony-forming cells function in vitro and in vivo[J].Blood Cells Mol Dis,2009,113(26):6716-6725
[41]Huang L C P,Grimes Br,Yoder Mc.Human umbilical cord blood plasma can replace fetal bovine serum for in vitro expansion of functional human endothelial colony-forming cells[J].Cytotherapy,2011,13(6):712-721
[42]Prasain N,Lee M R,Vemula S,et al.Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells[J].Nat Biotechnol,2014,32(11):1151-1157
[2]Hernandez-Lopez R,Chavez-Gonzalez A,Torres-Barrera P,et al.Reduced proliferation of endothelial colony-forming cells in unprovoked venous thromboembolic disease as a consequence of endothelial dysfunction[J].PLoS One,2017,12(9):e0183827
[3]Edwards N,Langford-Smith A W W,Wilkinson F L,et al.Endothelial Progenitor Cells:New Targets for Therapeutics for Inflammatory Conditions With High Cardiovascular Risk[J].Front Med(Lausanne),2018,5:200
[4]Lee Jy M Y,Lee Ho,Park Ak,et al.Deregulation of Retinaldehyde Dehydrogenase 2 Leads to Defective Angiogenic Function of Endothelial Colony Forming Cells in Pediatric Moyamoya Disease[J].Arterioscler Thromb Vasc Biol,2015,35(7):1670-1677
[5]Krieter Dh F R,Merget K,Lemke Hd,et al.Endothelial progenitor cells in patients on extracorporeal maintenance dialysis therapy.[J].Nephrol Dial Transplant,2010,25(12):4023-4031
[6]Munoz-Hernandez R,Miranda M L,Stiefel P,et al.Decreased Level of Cord Blood Circulating Endothelial Colony-Forming Cells in Preeclampsia[J].Hypertension,2014,64(1):165-171
[7]Ingram D A,Lien I Z,Mead L E,et al.In vitro hyperglycemia or a diabetic intrauterine environment reduces neonatal endothelial colony-forming cell numbers and function[J].Diabetes,2008,57(3):724-731
[8]Baker C D,Ryan S L,Ingram D A,et al.Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia[J].Am J Respir Crit Care Med,2009,180(5):454-461
[9]Fujinaga H F,Watanabe N,Kato T,et al.Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia[J].Am J Physiol Lung Cell Mol Physiol,2016,310(11):L1143-1154
[10]Peters B A,Diaz L A,Polyak K,et al.Contribution of bone marrowderived endothelial cells to human tumor vasculature[J].Nat Med,2005,11(3):261-262
[11]Mcallister S S,Weinberg R A.The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis[J].Nat Cell Biol,2014,16(8):717-727
[12]Francesco Moccia V F,Richard Tancredi,Matteo Giovanni Della Porta,et al.Breast and renal cancerd Derived endothelial colony forming cells share a common gene signature[J].European Journal of Cancer,2017,77:155-164
[13]Duong Van Huyen Jp S D,Bruneval P,Gaussem P,et al.Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia[J].Mod Pathol,2008,21(7):837-846
[14]Sarlon G,Zemani F,David L,et al.Therapeutic effect of fucoidan-stimulated endothelial colony-forming cells in peripheral ischemia[J].J Thromb Haemost,2012,10(1):38-48
[15]Moubarik C,Guillet B,Youssef B,et al.Transplanted Late Outgrowth Endothelial Progenitor Cells as Cell Therapy Product for Stroke[J].Stem Cell Reviews and Reports,2010,7(1):208-220
[16]Lee S H,Lee J H,Asahara T,et al.Genistein promotes endothelial colony-forming cell(ECFC)bioactivities and cardiac regeneration in myocardial infarction[J].PLo S One,2014,9(5):e96155
[17]Alphonse R S,Vadivel A,Fung M,et al.Existence,functional impairment,and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth[J].Circulation,2014,129(21):2144-2157
[18]Milbauer L C,Enenstein J A,Roney M,et al.Blood outgrowth endothelial cell migration and trapping in vivo:a window into gene therapy[J].Transl Res,2009,153(4):179-189
[19]Kim S-W,Jin H L,Kang S-M,et al.Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair[J].International Journal of Cardiology,2016,203:498-507
[20]Xin-Tao Huang,Y-Q Z,Sheng-Jie Li,et al.Intracerebroventricular Transplantation of ex vivo Expanded Endothelial Colony-Forming Cells Restores Blood Brain Barrier Integrity and Promotes Angiogenesis of Mice with Traumatic Brain Injury[J].J Neurotrauma,2013,30(24):2080-2088
[21]Zemani F,Silvestre J S,Fauvel-Lafeve F,et al.Ex vivo priming of endothelial progenitor cells with SDF-1 before transplantation could increase their proangiogenic potential[J].Arterioscler Thromb Vasc Biol,2008,28(4):644-650
[22]Jun Hee Lee1 S H L,Sung Hyun Choi1,Takayuki Asahar,et al.The Sulfated Polysaccharide Fucoidan Rescues Senescence of Endothelial Colony Forming Cells for Ischemic Repair[J].Stem Cells,2015,33(6):1939-1951
[23]Bennis Y,Sarlon-Bartoli G,Guillet B,et al.Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential[J].J Thromb Haemost,2012,10(9):1914-1928
[24]Sang Hun Lee J H L,Yong-Seok Han,Jung Min Ryu,et al.Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis[J].Stem Cell Research&Therapy,2015,6(1):139
[25]Mena H A,Zubiry P R,Dizier B,et al.Acidic preconditioning of endothelial colony-forming cells(ECFC)promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo[J].Stem Cell Res Ther,2018,9(1):120
[26]Lee S H,Lee K B,Lee J H,et al.Selective Interference Targeting of Lnk in Umbilical Cord-Derived Late Endothelial Progenitor Cells Improves Vascular Repair,Following Hind Limb Ischemic Injury,via Regulation of JAK2/STAT3 Signaling[J].Stem Cells,2015,33(5):1490-500
[27]Falabella Af S L,Valencia Ic,Eaglstein Wh.The use of tissueengineered skin(Apligraf)to treat a newborn with epidermolysis bullosa[J].Arch Dermatol,1999,135(10):1219-1222
[28]Ando W,Tateishi K,Hart D A,et al.Cartilage repair using an in vitro generated scaffold-free tissue-engineered construct derived from porcine synovial mesenchymal stem cells[J].Biomaterials,2007,28(36):5462-5470
[29]Fu J,Wang D A.In Situ Organ-Specific Vascularization in Tissue Engineering[J].Trends Biotechnol,2018,36(8):834-849
[30]Jung H S,Kim M J,Hong S H,et al.The potential of endothelial colony-forming cells to improve early graft loss after intraportal islet transplantation[J].Cell Transplant,2014,23(3):273-783
[31]Traktuev D O,Prater D N,Merfeld-Clauss S,et al.Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells[J].Circ Res,2009,104(12):1410-1420
[32]Goerke Sm O J,Plaha J,Stark Gb,et al.Endothelial progenitor cells from peripheral blood support bone regeneration by provoking an angiogenic response[J].Microvasc Res,2015,98:40-47
[33]Laurenzana A B A,D'alessio S,Bianchini F,et al.Melanoma cell therapy:Endothelial progenitor cells as shuttle of the MMP12uPAR-degrading enzyme[J].Oncotarget,2014,5(11):3711-3727
[34]Margheri G Z A,Olmi R,Trigari S,et al.Tumor-tropic endothelial colony forming cells(ECFCs)loaded with near-infrared sensitive Au nanoparticles:A"cellular stove"approach to the photoablation of melanoma[J].Oncotarget,2016,7(26):39846-39860
[35]Bodempudi V O J,Terai K,Zamora Ea,et al.Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors[J].Cancer Gene Ther,2010,17(12):855-863
[36]Wei J W J,Nakamura T,Stiller D,et al.Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas[J].Gene Ther,2007,14(22):1573-1586
[37]Melero-Martin Jm D O M,Allen P,Dudley Ac,et al.Host Myeloid Cells Are Necessary for Creating Bioengineered Human Vascular Networks in Vivo[J].Tissue Eng Part A,2010,16(8):2457-2466
[38]Naima Souidi M S,Juliane Rudeck,Dirk Strunk,et al.Stromal Cells Act as Guardians for Endothelial Progenitors by Reducing their Immunogenicity after Cotransplantation[J].STEM CELLS,2017,35(5):1233-1245
[39]Burnouf T,Strunk D,Koh M B,et al.Human platelet lysate:Replacing fetal bovine serum as a gold standard for human cell propagation?[J].Biomaterials,2016,76:371-387
[40]Reinisch A H N,Obenauf Ac,Kashofer K,et al.Humanized large-scale expanded endothelial colony-forming cells function in vitro and in vivo[J].Blood Cells Mol Dis,2009,113(26):6716-6725
[41]Huang L C P,Grimes Br,Yoder Mc.Human umbilical cord blood plasma can replace fetal bovine serum for in vitro expansion of functional human endothelial colony-forming cells[J].Cytotherapy,2011,13(6):712-721
[42]Prasain N,Lee M R,Vemula S,et al.Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells[J].Nat Biotechnol,2014,32(11):1151-1157