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Published online on June 10, 2005, 10.1073/pnas.0502678102

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Medical Sciences
Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

( cardiac stem cells | myocardial infarction | myocardial regeneration )

Axel Linke *{dagger}, Patrick Müller *{dagger}, Daria Nurzynska *, Claudia Casarsa *, Daniele Torella *, Angelo Nascimbene *, Clotilde Castaldo *, Stefano Cascapera *, Michael Böhm {ddagger}, Federico Quaini *, Konrad Urbanek *, Annarosa Leri *, Thomas H. Hintze *, Jan Kajstura *, and Piero Anversa *{sect}

*Cardiovascular Research Institute, Departments of Medicine and Physiology, New York Medical College, Valhalla, NY 10595; and {ddagger}Department of Medicine, University of Saarland, 66421 Homburg, Germany

Communicated by Eugene Braunwald, Brigham and Women's Hospital, Boston, MA, March 31, 2005 (received for review December 21, 2004)

The purpose of this study was to determine whether the heart in large mammals contains cardiac progenitor cells that regulate organ homeostasis and regenerate dead myocardium after infarction. We report that the dog heart possesses a cardiac stem cell pool characterized by undifferentiated cells that are self-renewing, clonogenic, and multipotent. These clonogenic cells and early committed progeny possess a hepatocyte growth factor (HGF)-c-Met and an insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated to induce their migration, proliferation, and survival. Therefore, myocardial infarction was induced in chronically instrumented dogs implanted with sonomicrometric crystals in the region of the left ventricular wall supplied by the occluded left anterior descending coronary artery. After infarction, HGF and IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor cells. This intervention led to the formation of myocytes and coronary vessels within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas {alpha}-sarcomeric actin, cardiac myosin heavy chain, troponin I, and {alpha}-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were also present. Myocardial reconstitution resulted in a marked recovery of contractile performance of the infarcted heart. In conclusion, the activation of resident primitive cells in the damaged dog heart can promote a significant restoration of dead tissue, which is paralleled by a progressive improvement in cardiac function. These results suggest that strategies capable of activating the growth reserve of the myocardium may be important in cardiac repair after ischemic injury.

Author contributions: A. Linke, P.M., A. Leri, T.H.H., J.K., and P.A. designed research; A. Linke, P.M., D.N., C. Casarsa, D.T., A.N., C. Castaldo, S.C., M.B., F.Q., K.U., A. Leri, T.H.H., and J.K. performed research; A. Linke, P.M., D.N., C. Casarsa, D.T., A.N., C. Castaldo, S.C., M.B., F.Q., K.U., A. Leri, T.H.H., J.K., and P.A. analyzed data; and A. Leri, T.H.H., J.K., and P.A. wrote the paper.

{dagger}A. Linke and P.M. contributed equally to this work.

{sect}To whom correspondence should be addressed at: Cardiovascular Research Institute, Department of Medicine, New York Medical College, Vosburgh Pavilion, Valhalla, NY 10595.

Piero Anversa, E-mail: piero_anversa{at}nymc.edu

www.pnas.org/cgi/doi/10.1073/pnas.0502678102
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