Skip to main content
Log in

Identification of a coronary stem cell in the human heart

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. 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

    Article  PubMed  CAS  Google Scholar 

  2. 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

    Article  CAS  Google Scholar 

  3. 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

    Article  PubMed  CAS  Google Scholar 

  4. 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

    PubMed  CAS  Google Scholar 

  5. 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.

  6. Jessup M, Brozena S (2003) Heart failure. N Engl J Med 348:2007–2018

    Article  PubMed  Google Scholar 

  7. Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91

    Article  PubMed  CAS  Google Scholar 

  8. 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

    Article  PubMed  CAS  Google Scholar 

  9. Ueno H, Weissman IL (2006) Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev Cell 11:519–533

    Article  PubMed  CAS  Google Scholar 

  10. 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

    Article  PubMed  CAS  Google Scholar 

  11. 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

    PubMed  CAS  Google Scholar 

  12. 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

    Article  PubMed  CAS  Google Scholar 

  13. 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

    Article  PubMed  CAS  Google Scholar 

  14. 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

    Article  PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. Coultas L, Chawengsaksophak K, Rossant J (2005) Endothelial cells and VEGF in vascular development. Nature 438:937–945

    Article  PubMed  CAS  Google Scholar 

  18. 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

    Article  PubMed  CAS  Google Scholar 

  19. Kinder SJ, Loebel DA, Tam PP (2001) Allocation and early differentiation of cardiovascular progenitors in the mouse embryo. Trends Cardiovasc Med 11:177–184

    Article  PubMed  CAS  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. 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

    Article  PubMed  CAS  Google Scholar 

  22. 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

    Article  PubMed  CAS  Google Scholar 

  23. Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in zebrafish. Science 298:2188–2190

    Article  PubMed  CAS  Google Scholar 

  24. 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

    Article  PubMed  CAS  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. 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

    PubMed  CAS  Google Scholar 

  27. Carmeliet P, Jain RK (2003) Angiogenesis in health and disease. Nat Med 9:653–660

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  PubMed  CAS  Google Scholar 

  29. 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

    PubMed  CAS  Google Scholar 

  30. 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

    Article  PubMed  Google Scholar 

  31. Hirschi KK, Ingram DA, Yoder MC (2008) Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 28:1584–1595

    Article  PubMed  CAS  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. Losordo DW, Dimmeler S (2004) Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation 109:2692–2697

    Article  PubMed  Google Scholar 

  34. 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

    Article  PubMed  Google Scholar 

  35. 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

    Article  PubMed  CAS  Google Scholar 

  36. Xiong JW (2008) Molecular and developmental biology of the hemangioblast. Dev Dyn 237:1218–1231

    Article  PubMed  CAS  Google Scholar 

  37. Pacilli A, Pasquinelli G (2009) Vascular wall resident progenitor cells: a review. Exp Cell Res 315:901–914

    Article  PubMed  CAS  Google Scholar 

  38. 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

    Article  PubMed  CAS  Google Scholar 

  39. 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

    Article  PubMed  CAS  Google Scholar 

  40. 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

    Article  PubMed  CAS  Google Scholar 

  41. 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

    Article  PubMed  CAS  Google Scholar 

  42. 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

    Article  PubMed  CAS  Google Scholar 

  43. 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

    Google Scholar 

  44. Montecino-Rodriguez E, Leathers H, Dorshkind K (2000) Expression of connexin 43 (Cx43) is critical for normal hematopoiesis. Blood 96:917–924

    PubMed  CAS  Google Scholar 

  45. 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

    PubMed  CAS  Google Scholar 

  46. 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

    Article  PubMed  CAS  Google Scholar 

  47. Leri A (2009) Human cardiac stem cells: the heart of a truth. Circulation 120:2515–2518

    Article  PubMed  Google Scholar 

  48. 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

    Article  PubMed  CAS  Google Scholar 

  49. Morrison SJ, Prowse KR, Ho P, Weissman IL (1996) Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5:207–216

    Article  PubMed  CAS  Google Scholar 

  50. 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

    Article  PubMed  CAS  Google Scholar 

  51. 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

    Article  PubMed  CAS  Google Scholar 

  52. Albrecht EW, Stegeman CA, Heeringa P, Henning RH, van Goor H (2003) Protective role of endothelial nitric oxide synthase. J Pathol 199:8–17

    Article  PubMed  Google Scholar 

  53. 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

    PubMed  CAS  Google Scholar 

  54. Yoshida T, Owens GK (2005) Molecular determinants of vascular smooth muscle cell diversity. Circ Res 96:280–291

    Article  PubMed  CAS  Google Scholar 

  55. van Eys GJ, Niessen PM, Rensen SS (2007) Smoothelin in vascular smooth muscle cells. Trends Cardiovasc Med 17:26–30

    Article  PubMed  Google Scholar 

  56. Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–1927

    Article  PubMed  CAS  Google Scholar 

  57. 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

    Article  PubMed  CAS  Google Scholar 

  58. Duan SZ, Usher MG, Mortensen RM (2009) PPARs: the vasculature, inflammation and hypertension. Curr Opin Nephrol Hypertens 18:128–133

    Article  PubMed  CAS  Google Scholar 

  59. 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

    Article  PubMed  CAS  Google Scholar 

  60. 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

    Article  Google Scholar 

  61. 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

    Article  PubMed  CAS  Google Scholar 

  62. 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

    Article  PubMed  CAS  Google Scholar 

  63. Schaper W (2009) Collateral circulation: past and present. Basic Res Cardiol 104:5–21

    Article  PubMed  CAS  Google Scholar 

  64. 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

    Article  PubMed  CAS  Google Scholar 

  65. 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

    Article  PubMed  CAS  Google Scholar 

  66. 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

    Article  PubMed  Google Scholar 

  67. 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

    Article  PubMed  CAS  Google Scholar 

  68. 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

    Article  PubMed  CAS  Google Scholar 

  69. McMurray JJ, Pfeffer MA (2005) Heart failure. Lancet 365:1877–1889

    Article  PubMed  Google Scholar 

  70. Sanderson WC, Scherbov S (2005) Average remaining lifetimes can increase as human populations age. Nature 435:811–813

    Article  PubMed  CAS  Google Scholar 

  71. Blackstone EH, Lytle BW (2000) Competing risks after coronary bypass surgery: the influence of death on reintervention. J Thorac Cardiovasc Surg 119:1221–1230

    Article  PubMed  CAS  Google Scholar 

  72. Hintze TH, Vatner SF (1984) Reactive dilation of large coronary arteries in conscious dogs. Circ Res 54:50–57

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Annarosa Leri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-011-0769-8

Keywords

Navigation