Abstract
Human ischemic cardiomyopathy is characterized by de novo cardiomyogenesis, which is limited to the surviving portion of the ventricle, and by organ hypertrophy that develops as a chronic response to ischemic injury. Although myocyte hypertrophy and myocyte regeneration restore the original myocardial mass, the coronary vasculature remains defective and the extent and regulation of myocardial perfusion are severely impaired. Recently, vascular stem cells (VSCs) have been identified in the coronary circulation. VSCs express c-kit and the vascular endothelial growth factor receptor-2, KDR. These cells are self-renewing, clonogenic, and multipotent in vitro and in vivo. In animal models of critical coronary artery stenosis, VSCs form large conductive coronary arteries and their distal branches. This degree of vasculogenesis replaces partly the function of the occluded coronary artery improving myocardial perfusion and positively interfering with the development of the post-infarction myopathy. Cell therapy directed to the restoration of the integrity of the coronary circulation, the replacement of atherosclerotic coronary vessels, or both, would change dramatically the goal of cell therapy for the ischemic heart: the prevention of myocardial injury would become the end-point of cell therapy rather than the partial recovery of established damage.
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Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P (1998) Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci USA 95:8801–8805
Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA et al (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Eng J Med 344:1750–1757
Urbanek K, Torella D, Sheikh F, De Angelis A, Nurzynska D, Silvestri F, Beltrami CA, Bussani R, Beltrami AP, Quaini F et al (2005) Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci USA 102:8692–8697
Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cigola E, Quaini F, Sonnenblick EH, Olivetti G, Anversa P (1994) Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation 89:151–163
Anversa P, Olivetti G (2002) Cellular basis of physiological and pathological myocardial growth. In: Handbook of physiology, the cardiovascular system, the heart. Bethesda, MD sect. 2 chapter 2:75–144.
Jessup M, Brozena S (2003) Heart failure. N Engl J Med 348:2007–2018
Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91
Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G (2004) Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432:625–630
Ueno H, Weissman IL (2006) Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev Cell 11:519–533
Ishii Y, Garriock RJ, Navetta AM, Coughlin LE, Mikawa T (2010) BMP signals promote proepicardial protrusion necessary for recruitment of coronary vessel and epicardial progenitors to the heart. Dev Cell 19:307–316
Kinder SJ, Tsang TE, Quinlan GA, Hadjantonakis AK, Nagy A, Tam PP (1999) The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo. Development 126:4691–4701
Bertrand JY, Chi NC, Santoso B, Teng S, Stainier DY, Traver D (2010) Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464:108–111
Boisset JC, van Cappellen W, Andrieu-Soler C, Galjart N, Dzierzak E, Robin C (2010) In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464:116–120
Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L, Bernstein A, Rossant J (1997) A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 89:981–990
Ema M, Faloon P, Zhang WJ, Hirashima M, Reid T, Stanford WL, Orkin S, Choi K, Rossant J (2003) Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes Dev 17:380–393
Ema M, Yokomizo T, Wakamatsu A, Terunuma T, Yamamoto M, Takahashi S (2006) Primitive erythropoiesis from mesodermal precursors expressing VE-cadherin, PECAM-1, Tie2, endoglin, and CD34 in the mouse embryo. Blood 108:4018–4024
Coultas L, Chawengsaksophak K, Rossant J (2005) Endothelial cells and VEGF in vascular development. Nature 438:937–945
Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM et al (2008) Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 453:524–528
Kinder SJ, Loebel DA, Tam PP (2001) Allocation and early differentiation of cardiovascular progenitors in the mouse embryo. Trends Cardiovasc Med 11:177–184
Jiang Y, Bn J, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M et al (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49
Hirai H, Ogawa M, Suzuki N, Yamamoto M, Breier G, Mazda O, Imanishi J, Nishikawa S (2003) Hemogenic and nonhemogenic endothelium can be distinguished by the activity of fetal liver kinase (Flk)-1 promoter/enhancer during mouse embryogenesis. Blood 101:886–893
Drenckhahn D, Schwarz QP, Gray S, Laskowski A, Kiriazis H, Ming Z, Harvey RP, Du XJ, Thorburn DR, Cox TC (2008) Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development. Dev Cell 15:521–533
Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in zebrafish. Science 298:2188–2190
Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD (2006) A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127:607–619
Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011) Transient regenerative potential of the neonatal mouse heart. Science 331:1078–1080
Olivetti G, Anversa P, Loud AV (1980) Morphometric study of early postnatal development in the left and right ventricular myocardium of the rat. II. Tissue composition, capillary growth, and sarcoplasmic alterations. Circ Res 46:503–512
Carmeliet P, Jain RK (2003) Angiogenesis in health and disease. Nat Med 9:653–660
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967
Ito H, Rovira II, Bloom ML, Takeda K, Ferrans VJ, Quyyumi AA, Finkel T (1999) Endothelial progenitor cells as putative targets for angiostatin. Cancer Res 59:5875–5877
Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600
Hirschi KK, Ingram DA, Yoder MC (2008) Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 28:1584–1595
Kim H, Kim SW, Nam D, Kim S, Yoon YS (2009) Cell therapy with bone marrow cells for myocardial regeneration. Antioxid Redox Signal 11:1897–1911
Losordo DW, Dimmeler S (2004) Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation 109:2692–2697
Yoon CH, Koyanagi M, Iekushi K, Seeger F, Urbich C, Zeiher AM, Dimmeler S (2010) Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: role of cardiovascular lineage commitment. Circulation 121:2001–2011
Ingram DA, Mead LE, Moore DB, Woodard W, Fenoglio A, Yoder MC (2005) Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 105:2783–2786
Xiong JW (2008) Molecular and developmental biology of the hemangioblast. Dev Dyn 237:1218–1231
Pacilli A, Pasquinelli G (2009) Vascular wall resident progenitor cells: a review. Exp Cell Res 315:901–914
Bearzi C, Leri A, Lo Monaco F, Rota M, Gonzalez A, Hosoda T, Pepe M, Qanud K, Ojaimi C, Bardelli S et al (2009) Identification of a coronary vascular progenitor cell in the human heart. Proc Natl Acad Sci USA 106:15885–15890
Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, Lecapitaine N et al (2007) Human cardiac stem cells. Proc Natl Acad Sci USA 104:14068–14073
Urbanek K, Cesselli D, Rota M, Nascimbene A, De Angelis A, Hosoda T, Bearzi C, Boni A, Bolli R, Kajstura J et al (2006) Stem cell niches in the adult mouse heart. Proc Natl Acad Sci USA 103:9226–9231
Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E (2004) Defining the epithelial stem cell niche in skin. Science 303:359–363
Hosoda T, Zheng H, Cabral-da-Silva M, Sanada F, Ide-Iwata N, Ogórek B, Ferreira-Martins J, Arranto C, D'Amario D, Del Monte F et al (2011) Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation 123:1287–1296
Cancelas JA, Koevoet WL, de Koning AE, Mayen AE, Rombouts EJ, Ploemacher RE (1996) Connexin-43 gap junctions are involved in multiconnexin-expressing stromal support of hemopoietic progenitors and stem cells. Blood 498:505
Montecino-Rodriguez E, Leathers H, Dorshkind K (2000) Expression of connexin 43 (Cx43) is critical for normal hematopoiesis. Blood 96:917–924
Blazsek I, Chagraoui J, Peault B (2000) Ontogenic emergence of the hematon, a morphogenetic stromal unit that supports multipotential hematopoietic progenitors in mouse bone marrow. Blood 96:3763–3771
Russo RE, Reali C, Radmilovich M, Fernández A, Trujillo-Cenóz O (2008) Connexin 43 delimits functional domains of neurogenic precursors in the spinal cord. J Neurosci 28:3298–3309
Leri A (2009) Human cardiac stem cells: the heart of a truth. Circulation 120:2515–2518
Hosoda T, D'Amario D, Cabral-Da-Silva MC, Zheng H, Padin-Iruegas ME, Ogorek B, Ferreira-Martins J, Yasuzawa-Amano S, Amano K, Ide-Iwata N et al (2009) Clonality of mouse and human cardiomyogenesis in vivo. Proc Natl Acad Sci USA 106:17169–17174
Morrison SJ, Prowse KR, Ho P, Weissman IL (1996) Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5:207–216
Mayshar Y, Rom E, Chumakov I, Kronman A, Yayon A, Benvenisty N (2008) Fibroblast growth factor 4 and its novel splice isoform have opposing effects on the maintenance of human embryonic stem cell self-renewal. Stem Cells 26:767–774
Levasseur DN, Wang J, Dorschner MO, Stamatoyannopoulos JA, Orkin SH (2008) Oct4 dependence of chromatin structure within the extended Nanog locus in ES cells. Genes Dev 22:575–580
Albrecht EW, Stegeman CA, Heeringa P, Henning RH, van Goor H (2003) Protective role of endothelial nitric oxide synthase. J Pathol 199:8–17
Hayward CP, Cramer EM, Song Z, Zheng S, Fung R, Massé JM, Stead RH, Podor TJ (1998) Studies of multimerin in human endothelial cells. Blood 91:1304–1317
Yoshida T, Owens GK (2005) Molecular determinants of vascular smooth muscle cell diversity. Circ Res 96:280–291
van Eys GJ, Niessen PM, Rensen SS (2007) Smoothelin in vascular smooth muscle cells. Trends Cardiovasc Med 17:26–30
Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–1927
Boni A, Urbanek K, Nascimbene A, Hosoda T, Zheng H, Delucchi F, Amano K, Gonzalez A, Vitale S, Ojaimi C et al (2008) Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci USA 105:15529–15534
Duan SZ, Usher MG, Mortensen RM (2009) PPARs: the vasculature, inflammation and hypertension. Curr Opin Nephrol Hypertens 18:128–133
Suzuki T, Aizawa K, Matsumura T, Nagai R (2005) Vascular implications of the Krüppel-like family of transcription factors. Arterioscler Thromb Vasc Biol 25:1135–1141
Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K et al (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:1–20
Linke A, Muller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A, Castaldo C, Cascapera S, Bohm M, Quaini F et al (2005) Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infracted myocardium, improving cardiac function. Proc Natl Acad Sci USA 102:8966–8971
Urbanek K, Rota M, Cascapera S, Bearzi C, Nascimbene A, De Angelis A, Hosoda T, Chimenti S, Baker M, Limana F et al (2005) Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infracted myocardium improving ventricular function and long-term survival. Circ Res 97:663–673
Schaper W (2009) Collateral circulation: past and present. Basic Res Cardiol 104:5–21
Tillmanns J, Rota M, Hosoda T, Misao Y, Esposito G, Gonzalez A, Vitale S, Parolin C, Yasuzawa-Amano S, Muraski J et al (2008) Formation of large coronary arteries by cardiac progenitor cells. Proc Natl Acad Sci USA 105:1668–1673
Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864
Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ (2004) Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110:3300–3305
Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL (2002) Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 277:38205–38211
Tacchini L, De Ponti C, Matteucci E, Follis R, Desiderio MA (2004) Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines. Carcinogenesis 25:2089–2100
McMurray JJ, Pfeffer MA (2005) Heart failure. Lancet 365:1877–1889
Sanderson WC, Scherbov S (2005) Average remaining lifetimes can increase as human populations age. Nature 435:811–813
Blackstone EH, Lytle BW (2000) Competing risks after coronary bypass surgery: the influence of death on reintervention. J Thorac Cardiovasc Surg 119:1221–1230
Hintze TH, Vatner SF (1984) Reactive dilation of large coronary arteries in conscious dogs. Circ Res 54:50–57
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Leri, A., Hosoda, T., Kajstura, J. et al. Identification of a coronary stem cell in the human heart. J Mol Med 89, 947–959 (2011). https://doi.org/10.1007/s00109-011-0769-8
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DOI: https://doi.org/10.1007/s00109-011-0769-8