心血管前体细胞诱导、增殖、分化及应用研究进展
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摘要
心血管前体细胞(CPCs)是指在胚胎发育过程或成体组织中存在的一类能够定向分化为心肌细胞(CMs)、内皮细胞(ECs)和血管平滑肌细胞(VSMCs)等具有特定分化潜能的前体细胞。应用多能干细胞(PSCs)定向诱导分化技术亦可在体外直接获得CPCs。CPCs不仅可为研究心血管细胞分化的分子机制提供细胞模型,而且还可以为其在再生医学研究及应用中提供大量的种子细胞来源。然而,人们对CPCs的诱导,自我更新及分化的调控机制仍知之甚少,因此,只有较全面地认识CPCs的各种生物学特性,才能在科研和临床中充分利用它们。本综述将重点阐述PSCs来源的CPCs的各种标志物及其诱导、增殖和定向分化为心血管细胞的相关信号调控机制及其在心血管疾病治疗应用中的最新进展,以期深入了解CPCs的生物学特性并为其在心血管再生医学中的应用提供理论基础。
Cardiovascular progenitor cells(CPCs)are multipotent stem cells with differentiation potential into cardiomyocytes(CMs), endothelial cells(ECs)and vascular smooth muscle cells(VSMCs)during embryonic development or in adult tissues. The application of pluripotent stem cells(PSCs)directed differentiation technology can also directly obtain CPCs in vitro. CPCs could not only provide a cell model for studying the molecular mechanism of differentiation of cardiovascular cells, but also a promising cell resource for cardiovascular regeneration. However, the mechanisms of induction, self-renewal and differentiation of CPCs are still incompletely understood, which limited their applications in cardiovascular cell therapy. This review will focus on the various markers of CPCs and the signaling regulation on CPCs induction, proliferation, differentiation, as well as the applications in cardiovascular regeneration.
Cardiovascular progenitor cells(CPCs)are multipotent stem cells with differentiation potential into cardiomyocytes(CMs), endothelial cells(ECs)and vascular smooth muscle cells(VSMCs)during embryonic development or in adult tissues. The application of pluripotent stem cells(PSCs)directed differentiation technology can also directly obtain CPCs in vitro. CPCs could not only provide a cell model for studying the molecular mechanism of differentiation of cardiovascular cells, but also a promising cell resource for cardiovascular regeneration. However, the mechanisms of induction, self-renewal and differentiation of CPCs are still incompletely understood, which limited their applications in cardiovascular cell therapy. This review will focus on the various markers of CPCs and the signaling regulation on CPCs induction, proliferation, differentiation, as well as the applications in cardiovascular regeneration.
引文
1 Birket MJ,Mummery CL.Pluripotent stem cell derived cardiovascular progenitors-A developmental perspective[J].Dev Biol,2015,400(2):169-179.
2 Le T,Chong J.Cardiac progenitor cells for heart repair[J].Cell Death Discov,2016,2:16052.
3 Zhou B,Wu SM.Reassessment of c-Kit in cardiac cells a complex interplay between expression,fate,and function[J].Circ Res,2018,123(1):9-11.
4 Maliken BD,Molkentin JD.Undeniable evidence that the adult mammalian heart lacks an endogenous regen-erative stem cell[J].Circulation,2018,138(8):806-808.
5 Waring CD,Vicinanza C,Papalamprou AA,et al.The adult heart responds to increased workload with physiologic hypertrophy,cardiac stem cell activation,and new myocyte formation[J].Eur Heart J,2014,35(39,SI):2722-2731.
6 Chiapparo G,Lin XH,Lescroart FA,et al.Mesp1 controls the speed,polarity,and directionality of cardiovascular progenitor migration[J].JCell Biol,2016,213(4):463-477.
7 Bondue A,T?nnler S,Chiapparo G,et al.Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation[J].J Cell Biol,2011,192(5):751-765.
8 Den Hartogh SC,Schreurs C,Monshouwer-Kloots JJ,et al.Dual reporter MESP1(mCherry/w)-NKX2-5(eGFP/w)hESCs enable studying early human cardiac differentiation[J].Stem Cells,2015,33(1):56-67.
9 Wu SM,Fujiwara Y,Cibulsky SM,et al.Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart[J].Cell,2006,127(6):1137-1150.
10 Watanabe Y,Zaffran S,Kuroiwa A,et al.Fibroblast growth factor 10gene regulation in the second heart field by Tbx1,Nkx2-5,and Islet1reveals a genetic Switch for down-regulation in the myocardium[J].Proc Natl Acad Sci U S A,2012,109(45):18273-18280.
11 Beltrami AP,Barlucchi L,Torella D,et al.Adult cardiac stem cells are multipotent and support myocardial regeneration[J].Cell,2003,114(6):763-776.
12 Nadal-Ginard B,Ellison GM,Torella D.Absence of evidence is not evidence of absence pitfalls of cre knock-ins in the c-Kit locus[J].Circ Res,2014,115(4):415-418.
13 van Berlo JH,Kanisicak O,Maillet M,et al.C-kit(+)cells minimally contribute cardiomyocytes to the heart[J].Nature,2014,509(7500):337-341.
14 Sultana N,Zhang L,Yan J,et al.Resident c-kit(+)cells in the heart are not cardiac stem cells[J].Nat Commun,2015,6:8701.
15 Liu QZ,Yang R,Huang XZ,et al.Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes[J].Cell Res,2016,26(1):119-130.
16 He L,Li Y,Li Y,et al.Enhancing the precision of genetic lineage tracing using dual recombinases[J].Nat Med,2017,23(12):1488-1498.
17 Yoon C,Song H,Yin T,et al.FZD4 marks lateral plate mesoderm and signals with NORRIN to increase cardiomyocyte induction from pluripotent stem Cell-Derived cardiac progenitors[J].Stem Cell Reports,2018,10(1):87-100.
18 Skelton RJ,Brady B,Khoja S,et al.CD13 and ROR2 permit isolation of highly enriched cardiac mesoderm from differentiating human embryonic stem cells[J].Stem Cell Reports,2016,6(1):95-108.
19 Skelton RJ,Costa M,Anderson DJ,et al.SIRPA,VCAM1 and CD34 identify discrete lineages during early human cardiovascular development[J].Stem Cell Res,2014,13(1):172-179.
20 Noseda M,Peterkin T,Sim?es FC,et al.Cardiopoietic factors:extracellular signals for cardiac lineage commitment[J].Circ Res,2011,108(1):129-152.
21 Cai WQ,Albini S,Wei K,et al.Coordinate nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment[J].Genes Dev,2013,27(21):2332-2344.
22 Cao N,Liang H,Huang J,et al.Highly efficient induction and longterm maintenance of multipotent cardiovascular progenitors from human pluripotent stem cells under defined conditions[J].Cell Res,2013,23(9):1119-1132.
23 Burridge PW,Keller G,Gold JD,et al.Production of de novo cardiomyocytes:human pluripotent stem cell differentiation and direct reprogramming[J].Cell Stem Cell,2012,10(1):16-28.
24 Sirbu IO,Zhao X,Duester G.Retinoic acid controls heart anteroposterior patterning by down-regulating Isl1 through the Fgf8pathway[J].Dev Dyn,2008,237(6):1627-1635.
25 Novikov N,Evans T.Tmem88a mediates GATA-dependent specification of cardiomyocyte progenitors by restricting WNTsignaling[J].Development,2013,140(18):3787-3798.
26 Zhang Y,Cao N,Huang Y,et al.Expandable cardiovascular progenitor cells reprogrammed from fibroblasts[J].Cell Stem Cell,2016,18(3):368-381.
27 Birket MJ,Ribeiro MC,Verkerk AO,et al.Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells[J].Nat Biotechnol,2015,33(9):970-979.
28 Lalit PA,Salick MR,Nelson DO,et al.Lineage reprogramming of fibroblasts into proliferative induced cardiac progenitor cells by defined factors[J].Cell Stem Cell,2016,18(3):354-367.
29 Puente BN,Kimura W,Muralidhar SA,et al.The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNAdamage response[J].Cell,2014,157(3):565-579.
30 Wang WE,Li L,Xia X,et al.Dedifferentiation,proliferation and redifferentiation of adult mammalian cardio-myocytes after ischemic injury[J].Circulation,2017,136(9):834-848.
31 Sinha S,Iyer D,Granata A.Embryonic origins of human vascular smooth muscle cells:implications for in vitro modeling and clinical application[J].Cell Mol Life Sci,2014,71(12):2271-2288.
32 Liu Y,Chen L,Diaz AD,et al.Mesp1 marked cardiac progenitor cells repair infarcted mouse hearts[J].Sci Rep,2016,6(1):1-14.
33 Zhu KY,Wu Q,Ni C,et al.Lack of remuscularization following transplantation of human embryonic stem cell-derived cardiovascular progenitor cells in infarcted nonhuman primates[J].Circ Res,2018,122(7):958-969.
34 Barile L,Milano G,Vassalli G.Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia[J].Stem Cell Investig,2017,4:93.
35 Menasche P,Vanneaux V,Hagege A,et al.Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment:first clinical case report[J].Eur Heart J,2015,36(30):2011-2017.
36 MenaschéP,Vanneaux V,Hagège A,et al.Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction[J].J Am Coll Cardiol,2018,71(4):429-438.
37 Trac D,Xu CH,Davis ME.Aggregation of child cardiac progenitor cells into spheres activates notch signaling and improves treatment of right ventricular heart failure[J].Circulation,2017,136(1):526-538.
2 Le T,Chong J.Cardiac progenitor cells for heart repair[J].Cell Death Discov,2016,2:16052.
3 Zhou B,Wu SM.Reassessment of c-Kit in cardiac cells a complex interplay between expression,fate,and function[J].Circ Res,2018,123(1):9-11.
4 Maliken BD,Molkentin JD.Undeniable evidence that the adult mammalian heart lacks an endogenous regen-erative stem cell[J].Circulation,2018,138(8):806-808.
5 Waring CD,Vicinanza C,Papalamprou AA,et al.The adult heart responds to increased workload with physiologic hypertrophy,cardiac stem cell activation,and new myocyte formation[J].Eur Heart J,2014,35(39,SI):2722-2731.
6 Chiapparo G,Lin XH,Lescroart FA,et al.Mesp1 controls the speed,polarity,and directionality of cardiovascular progenitor migration[J].JCell Biol,2016,213(4):463-477.
7 Bondue A,T?nnler S,Chiapparo G,et al.Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation[J].J Cell Biol,2011,192(5):751-765.
8 Den Hartogh SC,Schreurs C,Monshouwer-Kloots JJ,et al.Dual reporter MESP1(mCherry/w)-NKX2-5(eGFP/w)hESCs enable studying early human cardiac differentiation[J].Stem Cells,2015,33(1):56-67.
9 Wu SM,Fujiwara Y,Cibulsky SM,et al.Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart[J].Cell,2006,127(6):1137-1150.
10 Watanabe Y,Zaffran S,Kuroiwa A,et al.Fibroblast growth factor 10gene regulation in the second heart field by Tbx1,Nkx2-5,and Islet1reveals a genetic Switch for down-regulation in the myocardium[J].Proc Natl Acad Sci U S A,2012,109(45):18273-18280.
11 Beltrami AP,Barlucchi L,Torella D,et al.Adult cardiac stem cells are multipotent and support myocardial regeneration[J].Cell,2003,114(6):763-776.
12 Nadal-Ginard B,Ellison GM,Torella D.Absence of evidence is not evidence of absence pitfalls of cre knock-ins in the c-Kit locus[J].Circ Res,2014,115(4):415-418.
13 van Berlo JH,Kanisicak O,Maillet M,et al.C-kit(+)cells minimally contribute cardiomyocytes to the heart[J].Nature,2014,509(7500):337-341.
14 Sultana N,Zhang L,Yan J,et al.Resident c-kit(+)cells in the heart are not cardiac stem cells[J].Nat Commun,2015,6:8701.
15 Liu QZ,Yang R,Huang XZ,et al.Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes[J].Cell Res,2016,26(1):119-130.
16 He L,Li Y,Li Y,et al.Enhancing the precision of genetic lineage tracing using dual recombinases[J].Nat Med,2017,23(12):1488-1498.
17 Yoon C,Song H,Yin T,et al.FZD4 marks lateral plate mesoderm and signals with NORRIN to increase cardiomyocyte induction from pluripotent stem Cell-Derived cardiac progenitors[J].Stem Cell Reports,2018,10(1):87-100.
18 Skelton RJ,Brady B,Khoja S,et al.CD13 and ROR2 permit isolation of highly enriched cardiac mesoderm from differentiating human embryonic stem cells[J].Stem Cell Reports,2016,6(1):95-108.
19 Skelton RJ,Costa M,Anderson DJ,et al.SIRPA,VCAM1 and CD34 identify discrete lineages during early human cardiovascular development[J].Stem Cell Res,2014,13(1):172-179.
20 Noseda M,Peterkin T,Sim?es FC,et al.Cardiopoietic factors:extracellular signals for cardiac lineage commitment[J].Circ Res,2011,108(1):129-152.
21 Cai WQ,Albini S,Wei K,et al.Coordinate nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment[J].Genes Dev,2013,27(21):2332-2344.
22 Cao N,Liang H,Huang J,et al.Highly efficient induction and longterm maintenance of multipotent cardiovascular progenitors from human pluripotent stem cells under defined conditions[J].Cell Res,2013,23(9):1119-1132.
23 Burridge PW,Keller G,Gold JD,et al.Production of de novo cardiomyocytes:human pluripotent stem cell differentiation and direct reprogramming[J].Cell Stem Cell,2012,10(1):16-28.
24 Sirbu IO,Zhao X,Duester G.Retinoic acid controls heart anteroposterior patterning by down-regulating Isl1 through the Fgf8pathway[J].Dev Dyn,2008,237(6):1627-1635.
25 Novikov N,Evans T.Tmem88a mediates GATA-dependent specification of cardiomyocyte progenitors by restricting WNTsignaling[J].Development,2013,140(18):3787-3798.
26 Zhang Y,Cao N,Huang Y,et al.Expandable cardiovascular progenitor cells reprogrammed from fibroblasts[J].Cell Stem Cell,2016,18(3):368-381.
27 Birket MJ,Ribeiro MC,Verkerk AO,et al.Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells[J].Nat Biotechnol,2015,33(9):970-979.
28 Lalit PA,Salick MR,Nelson DO,et al.Lineage reprogramming of fibroblasts into proliferative induced cardiac progenitor cells by defined factors[J].Cell Stem Cell,2016,18(3):354-367.
29 Puente BN,Kimura W,Muralidhar SA,et al.The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNAdamage response[J].Cell,2014,157(3):565-579.
30 Wang WE,Li L,Xia X,et al.Dedifferentiation,proliferation and redifferentiation of adult mammalian cardio-myocytes after ischemic injury[J].Circulation,2017,136(9):834-848.
31 Sinha S,Iyer D,Granata A.Embryonic origins of human vascular smooth muscle cells:implications for in vitro modeling and clinical application[J].Cell Mol Life Sci,2014,71(12):2271-2288.
32 Liu Y,Chen L,Diaz AD,et al.Mesp1 marked cardiac progenitor cells repair infarcted mouse hearts[J].Sci Rep,2016,6(1):1-14.
33 Zhu KY,Wu Q,Ni C,et al.Lack of remuscularization following transplantation of human embryonic stem cell-derived cardiovascular progenitor cells in infarcted nonhuman primates[J].Circ Res,2018,122(7):958-969.
34 Barile L,Milano G,Vassalli G.Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia[J].Stem Cell Investig,2017,4:93.
35 Menasche P,Vanneaux V,Hagege A,et al.Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment:first clinical case report[J].Eur Heart J,2015,36(30):2011-2017.
36 MenaschéP,Vanneaux V,Hagège A,et al.Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction[J].J Am Coll Cardiol,2018,71(4):429-438.
37 Trac D,Xu CH,Davis ME.Aggregation of child cardiac progenitor cells into spheres activates notch signaling and improves treatment of right ventricular heart failure[J].Circulation,2017,136(1):526-538.