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Cardiac stem cells: isolation, expansion and experimental use for myocardial regeneration

Abstract

Cellular cardiomyoplasty (myogenic cell grafting) is actively being explored as a novel method to regenerate damaged myocardium. The adult human heart contains small populations of indigenous committed cardiac stem cells or multipotent cardiac progenitor cells, identified by their cell-surface expression of c-kit (the receptor for stem cell factor), P-glycoprotein (a member of the multidrug resistance protein family), and Sca-1 (stem cell antigen 1, a mouse hematopoietic stem cell marker) or a Sca-1-like protein. Cardiac stem cells represent a logical source to exploit in cardiac regeneration therapy because, unlike other adult stem cells, they are likely to be intrinsically programmed to generate cardiac tissue in vitro and to increase cardiac tissue viability in vitro. Cardiac stem cell therapy could, therefore, change the fundamental approach to the treatment of heart disease.

Key Points

  • Use of flow cytometry to sort cells with specific surface markers allows the identification of defined cell populations with an inducible differentiated phenotype and the potential for cardiac regeneration

  • Clinical translation of sorted stem cells, however, requires improved recruitment and induction by growth factors and cytokines

  • Isolation of cardiac stem cells by exploiting their functional properties (migration capacity, three-dimensional growth in culture) allows the expansion of a heterogeneous and spontaneously differentiating cell population from a very small sample

  • Clinical translation requires the isolation of cardiac stem cells from surgical or biopsy samples, ex vivo expansion, and reinjection into the damaged heart for autologous cell cardiomyoplasty

  • The three-dimensional self-organization of the cardiac stem cells in culture, comprising a core of proliferating progenitor cells protected by external layers of more-differentiated cells, allows a physiologic relationship between the cells and their environment

  • The three-dimensional organization of the cardiac stem cells could improve their survival and engraftment, once injected into the damaged heart

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Figure 1: Morphology of the isolated human cardiospheres
Figure 2: Phenotype of the isolated human cardiospheres

References

  1. Anversa P et al. (2006) Life and death of cardiac stem cells: a paradigm shift in cardiac biology. Circulation 113: 1451–1463

    Article  Google Scholar 

  2. Beltrami AP et al. (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344: 1750–1757

    CAS  Article  Google Scholar 

  3. Nadin BM et al. (2003) Phenotype and hematopoietic potential of side population cells throughout embryonic development. Blood 102: 2436–2443

    CAS  Article  Google Scholar 

  4. Vergier B et al. (1993) Expression of MDR1/P glycoprotein in human sarcomas. Br J Cancer 68: 1221–1226

    CAS  Article  Google Scholar 

  5. Hierlihy AM et al. (2002) The post-natal heart contains a myocardial stem cell population. FEBS Lett 530: 239–243

    CAS  Article  Google Scholar 

  6. Martin CM et al. (2004) Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 265: 262–275

    CAS  Article  Google Scholar 

  7. Pfister O et al. (2004) CD31 but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 97: 52–61

    Article  Google Scholar 

  8. Beltrami AP et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763–776

    CAS  Article  Google Scholar 

  9. Dawn B et al. (2005) Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 102: 3766–3771

    CAS  Article  Google Scholar 

  10. Oh H et al. (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 100: 12313–12318

    CAS  Article  Google Scholar 

  11. Matsuura K et al. (2004) Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes. J Biol Chem 279: 11384–11391

    CAS  Article  Google Scholar 

  12. Leri A et al. (2005) Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85: 1373–1416

    CAS  Article  Google Scholar 

  13. Laugwitz KL et al. (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433: 647–653

    CAS  Article  Google Scholar 

  14. Cai J et al. (2004) In search of “stemness”. Exp Hematol 32: 585–598

    Article  Google Scholar 

  15. Mouquet F et al. (2005) Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem cells. Circ Res 97: 1090–1092

    CAS  Article  Google Scholar 

  16. Messina E et al. (2004) Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 95: 911–921

    CAS  Article  Google Scholar 

  17. Rossi MI et al. (2005) Multicellular spheroids of bone marrow stromal cells: a three-dimensional in vitro culture system for the study of hematopoietic cell migration. Braz J Med Biol Res 38: 1455–1462

    CAS  Article  Google Scholar 

  18. Armstrong MT et al. (2000) Regulation of proliferation of the fetal myocardium. Dev Dyn 219: 226–236

    CAS  Article  Google Scholar 

  19. Bates RC et al. (2000) Spheroids and cell survival. Crit Rev Oncol Hematol 36: 61–74

    CAS  Article  Google Scholar 

  20. Cerisoli F et al. c-kit-positive cardiac stem cells (CSCs) can be generated in damaged heart from bone marrow-derived cells [abstract 13230]. Circulation 114 (Suppl 18)

  21. Barile L et al. (2005) Engraftment, migration and functional improvement in ischemic mouse hearts injected with human cardiosphere-derived stem cells. Late-Breaking Basic Science Abstracts. Presented at the American Heart Association Scientific Sessions 2005, 2005 November 1316, Dallas Convention Center, Dallas, TX. Circ Res doi:10.1161/01.RES.0000196463.09130.2b

  22. Smith RR et al. (2005) Electrophysiology of human and porcine adult cardiac stem cells isolated from endomyocardial biopsies. Late-breaking developments in stem cell biology and cardiac growth regulation. Circulation 111: 1720

    Article  Google Scholar 

  23. Pozzi D et al. Extremely low frequency magnetic field promotes differentiation of the ex vivo expanded human cardiac stem cells. Proceedings of the Biological Effects of Electromagnetic Fields 4th International Workshop: 2006 16–20 October, Crete, Greece, 928–931 (Ed. P Kostarakis), in press

  24. Liboff AR (2004) Toward an electromagnetic paradigm for biology and medicine. J Altern Complement Med 10: 41–47

    Article  Google Scholar 

  25. Zhadin M and Barnes F (2005) Frequency and amplitude windows in the combined action of DC and low frequency AC magnetic fields on ion thermal motion in a macromolecule: theoretical analysis. Bioelectromagnetics 26: 323–330

    CAS  Article  Google Scholar 

  26. Korff T and Augustin HG (1998) Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation. J Cell Biol 143: 1341–1352

    CAS  Article  Google Scholar 

  27. Urbanek K et al. (2006) Stem cell niches in the adult mouse heart. Proc Natl Acad Sci USA 103: 9226–9231

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the Ministero della Pubblica Istruzione, Università e Ricerca (MIUR) and by a grant from the Istituto Pasteur-Fondazione Cenci Bolognetti to the Department of Experimental Medicine, University of Rome “La Sapienza”.

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Correspondence to Alessandro Giacomello.

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Barile, L., Chimenti, I., Gaetani, R. et al. Cardiac stem cells: isolation, expansion and experimental use for myocardial regeneration. Nat Rev Cardiol 4 (Suppl 1), S9–S14 (2007). https://doi.org/10.1038/ncpcardio0738

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