Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The adult human heart as a source for stem cells: repair strategies with embryonic-like progenitor cells

Nature Clinical Practice Cardiovascular Medicine volume 4, pages S27–S39 (2007)Cite this article

Abstract

Adequate cell-based repair of adult myocardium remains an elusive goal because most cells that are used cannot generate mature myocardium sufficient to promote large functional improvements. Embryonic stem cells can generate both mature cardiocytes and vasculature, but their use is hampered by associated teratoma formation and the need for an allogeneic source. The detection of sca-1+, c-kit+, or isl-1+ cardiac precursors and the creation of cardiospheres from adult heart tissues suggest that a persistent population of immature progenitor cells is present in the mature myocardium. These cell populations probably represent stages along a continuum of cardiac stem cell development and differentiation. We report isolation from ventricle of uncommitted cardiac progenitor cells, which appear to resemble the more immature, common pool of embryonic lateral plate mesoderm progenitors that yield both myocardial and endocardial cells during normal cardiac development. Under controlled in vitro conditions and in vivo, these cells can differentiate into endothelial, smooth muscle, and cardiomyocyte lineages and can be isolated and expanded to clinically relevant numbers from adult rat myocardial tissue. In this article, we discuss the potential for autologous repair or even cardiac regeneration with cells that follow a developmental pathway similar to embryonic cardiac precursors but without the inherent limitations associated with undifferentiated embryonic stem cells.

Key Points

  • Uncommitted cardiac-derived progenitor cells (UPCs) can be isolated from adult mammalian heart and expanded in vitro

  • UPCs resemble undifferentiated embryonic stem cells and recapitulate cardiac development when exposed to cardiac differentiation conditions in vitro

  • These cells may give rise to other cardiac stem cell populations

  • UPCs improve left ventricular function when transplanted after myocardial injury and differentiate into cardiomyocyte-like and vascular cells

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SSEA-1+ progenitor cells in rat postnatal myocardia
Figure 2: Characterization of adult heart-derived progenitor cells isolated from primary cultures
Figure 3: Schematic representations of in vitro recapitulation of cardiac development of and application of UPCs
Figure 4: Primary culture of ventricular mechanically and enzymatically processed rat ventricular myocardium
Figure 5: In vitro differentiation of adult heart-derived UPCs with cardiocyte coculture
Figure 6: Functional repair and myocardial regeneration after undifferentiated progenitor cell transplantation in a rat left anterior descending coronary artery ligation model
Figure 7: Left ventricular function and remodeling after treatment with UCPs, compared with control

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Laflamme MA et al. (2002) Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res 90: 634–640

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Linke A et al. (2005) Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci USA 102: 8966–8971

    Article  CAS  Google Scholar 

  6. Urbanek K et al. (2003) Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci USA 100: 10440–10445

    Article  CAS  Google Scholar 

  7. Urbanek K 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  CAS  Google Scholar 

  8. Rosenblatt-Velin N et al. (2005) FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes. J Clin Invest 115: 1724–1733

    Article  CAS  Google Scholar 

  9. 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

    Article  CAS  Google Scholar 

  10. 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

    Article  CAS  Google Scholar 

  11. Pfister O et al. (2005) CD31− but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 97: 52–61

    Article  CAS  Google Scholar 

  12. Urbanek K et al. (2005) Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ Res 97: 663–673

    Article  CAS  Google Scholar 

  13. 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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Zhou S et al. (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7: 1028–1034

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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 

  19. Solter D and Knowles BB (1978) Monoclonal antibody defining a stage-specific mouse embryonic antigen (SSEA-1). Proc Natl Acad Sci USA 75: 5565–5569

    Article  CAS  Google Scholar 

  20. Vassilieva S et al. (2000) Establishment of SSEA-1- and Oct-4-expressing rat embryonic stem-like cell lines and effects of cytokines of the IL-6 family on clonal growth. Exp Cell Res 258: 361–373

    Article  CAS  Google Scholar 

  21. Durcova-Hills G et al. (2001) Pluripotential stem cells derived from migrating primordial germ cells. Differentiation 68: 220–226

    Article  CAS  Google Scholar 

  22. Scholer HR et al. (1989) A family of octamer-specific proteins present during mouse embryogenesis: evidence for germline-specific expression of an Oct factor. EMBO J 8: 2543–2550

    Article  CAS  Google Scholar 

  23. Reubinoff BE et al. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18: 399–404

    Article  CAS  Google Scholar 

  24. Fraser ST et al. (2002) Definitive hematopoietic commitment within the embryonic vascular endothelial-cadherin+ population. Exp Hematol 30: 1070–1078

    Article  CAS  Google Scholar 

  25. Iida M et al. (2005) Identification of cardiac stem cells with FLK1, CD31, and VE-cadherin expression during embryonic stem cell differentiation. FASEB J 19: 371–378

    Article  CAS  Google Scholar 

  26. Kataoka H et al. (1997) Expressions of PDGF receptor alpha, c-Kit and Flk1 genes clustering in mouse chromosome 5 define distinct subsets of nascent mesodermal cells. Dev Growth Differ 39: 729–740

    Article  CAS  Google Scholar 

  27. Minasi MG et al. (2002) The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development 129: 2773–2783

    CAS  PubMed  Google Scholar 

  28. Cai CL et al. (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5: 877–889

    Article  CAS  Google Scholar 

  29. Durocher D et al. (1997) The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J 16: 5687–5696

    Article  CAS  Google Scholar 

  30. Tanaka M et al. (1999) The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 126: 1269–1280

    CAS  PubMed  Google Scholar 

  31. Amit M et al. (2004) Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod 70: 837–845

    Article  CAS  Google Scholar 

  32. Yamashita JK et al. (2005) Prospective identification of cardiac progenitors by a novel single cell-based cardiomyocyte induction. FASEB J 19: 1534–1536

    Article  CAS  Google Scholar 

  33. Ratajska A et al. (2001) Differentiation of the smooth muscle cell phenotypes during embryonic development of coronary vessels in the rat. Histochem Cell Biol 116: 79–87

    CAS  PubMed  Google Scholar 

  34. Muller-Ehmsen J et al. (2002) Rebuilding a damaged heart: long-term survival of transplanted neonatal rat cardiomyocytes after myocardial infarction and effect on cardiac function. Circulation 105: 1720–1726

    Article  Google Scholar 

  35. Erdo F et al. (2003) Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab 23: 780–785

    Article  Google Scholar 

  36. Kofidis T et al. (2005) Stimulation of paracrine pathways with growth factors enhances embryonic stem cell engraftment and host-specific differentiation in the heart after ischemic myocardial injury. Circulation 111: 2486–2493

    Article  CAS  Google Scholar 

  37. Laflamme MA and Murry CE (2005) Regenerating the heart. Nat Biotechnol 23: 845–856

    Article  CAS  Google Scholar 

  38. Ott HC et al. (2004) Combined transplantation of skeletal myoblasts and bone marrow stem cells for myocardial repair in rats. Eur J Cardiothorac Surg 25: 627–634

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. J Brechtken is a Fellow in Cardiology in the Division of Cardiology, and DA Taylor is Medtronic Bakken Professor in the Department of Integrative Biology and Physiology, Department of Surgery, HC Ott formerly was Scientific Director, TS Matthiesen, S Grindle, and W Nelson are scientists, S-K Goh is an assistant scientist, and DA Taylor is Director in the Center for Cardiovascular Repair, University of Minnesota, MN, USA. HC Ott is currently a resident in general surgery, Massachusetts General Hospital, Boston, MA, USA.,

    Harald C Ott, Thomas S Matthiesen, Johannes Brechtken, Suzanne Grindle, Saik-Kia Goh, Wendy Nelson & Doris A Taylor

Authors
  1. Harald C Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas S Matthiesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johannes Brechtken
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suzanne Grindle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Saik-Kia Goh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wendy Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Doris A Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Doris A Taylor.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ott, H., Matthiesen, T., Brechtken, J. et al. The adult human heart as a source for stem cells: repair strategies with embryonic-like progenitor cells. Nat Rev Cardiol 4 (Suppl 1), S27–S39 (2007). https://doi.org/10.1038/ncpcardio0771

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio0771

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing