ENDOGENOUS CARDIAC STEM CELLS IN THE REGENERATION OF ACUTE AND CHRONIC ISCHEMIC MYOCARDIUM

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1 ENDOGENOUS CARDIAC STEM CELLS IN THE REGENERATION OF ACUTE AND CHRONIC ISCHEMIC MYOCARDIUM Bernardo Nadal-Ginard, M.D., Ph.D. New York Medical College Angioplasty Summit 2004, Seoul 04/29/04

2 MYOCARDIAL REGENERATION Cardiac failure is often the consequence of the loss or irreversible damage of an important fraction of the ventricular myocytes Until now all the protocols to treat cardiac failure and also to induce myocardial regeneration are based on the premise that the endogenous regenerative capacity of the myocardium is either non-existent or very limited. For that reason, it is believed that to replace the lost muscular mass requires cellular transplantation This situation, at least in part, is based in an obsolete concept of the myocardium and it has limited the therapeutical options

3 MYOCARDIAL REGENERATION Cardiac regeneration using different exogenous stem cells EPCs, BMCs, etc appear to be successful in improving myocardial performance and have proven the feasibility of this therapeutic approach The techniques are complex, time consuming, expensive, require sophisticated instrumentation, and will be available to a very limited number of patients in a limited number of centers To make myocardial regeneration therapies available to the millions of patient candidates will require simpler and cheaper approaches that use off-the-shelf regenerating agents that can be administered in the course of a standard catheterization procedure

4 Current View of Cardiac Homeostasis New Myocyte Formation Myocardial Mass (Terminally Differentiated Myocytes) Myocyte Loss

5 If the heart is a terminally differentiated organ without self-renewal properties, to preserve cardiac mass through life requires that: Cardiocyte death should be very rare. In the absence of self-renewal even very slow rates of cell death would result in severe loss of cardiac mass through life. There should be no new myocyte formation Each and every one of the cardiocytes should be as old as the individual.

6 Cell Death & Regeneration after MI Beltrami et al. NEJM 344: (2001)

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8 CSCs in the Ventricle

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12 THE MYOCARDIUM HAS INTRINSIC REGENERATIVE CAPACITY The myocardium has significant intrinsic regenerative capacity. However, due to apoptosis of the CSCs, in most cases this regeneration it is not sufficient to replace the myocardial mass lost in a MI and/or prevent the formation of a scar. If these primitive myocardial cell are true stem cells, can we stimulate them to become more efficient in the regeneration of the lost myocardium?

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17 MYOCARDIAL REGENERATION Total of 5x10 5 cloned CSCs injected per heart 24 hours survival of injected cells: ~5-10% New myocytes regenerated in two weeks: ~12x10 6 Non-myocyte cells (arteries, veins, and capillaries) regenerated from the injected cells: ~36x10 6 Ratio of regenerated cells to surviving injected cells: 1:1160 to 1:2320

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22 Knowing the heart possesses an intrinsic regenerative capacity, do we really need to manipulate the CSCs outside the body to produce myocardial regeneration? Does the heart require exogenous cardiac or non-cardiac stem cells or can the endogenous CSCs be stimulated to amplify and differentiate in situ? The CSCs have receptors for many anti apoptotic, growth and chemotactic factors. In vitro, the combination of IGF1 and HGF is effective in stimulating and mobilizing these cells.

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29 MOBILIZATION OF ADULT CARDIAC STEM CELLS Mobilization with growth factors produces an increase of stem cells in the infarcted zone In 10 days, the activated stem cells regenerate the myocytes and coronary vessels lost in an infarct of 65% of the left ventricular mass The new muscle cells are small but structurally, functionally and biochemically normal and resemble young myocytes Therefore, it is possible and practical to induce functionally meaningful cardiac regeneration by stimulating the intrinsic cardiac regenerative capacity without the need to introduce new cells into the myocardium

30 Is it possible to use a similar protocol to improve chronic heart failure secondary to diffuse myocardial damage?

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34 Cardiac Stem Cell Stimulated in situ

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40 Adult Cardiac Homeostasis Stem and Progenitor Cells Dying Myocytes Cycling Immature Myocytes Myocardial Mass (Non-replicating, Terminally Differentiated Myocytes) Aging Myocytes p16 pos

41 Main Conclusions 1. Although the myocardium is mainly composed of myocytes that cannot divide, the heart has a potent intrinsic regenerative capacity. It contains CSCs able to regenerate myocytes and vasculature 2. Therapy with exogenous cells will likely produce clinical improvement. However, there seem to be an alternative to the introduction of exogenous cells to produce myocardial regeneration. Stimulation of the endogenous stem cells appears to be sufficient 3. The challenge is to learn how to manipulate the CSCs in a clinically useful, simple, and economical way.

42 ACKNOWLEDGMENTS Antonio Beltrami Danielle Torella Laura Barlucchi Federica Limana Stefano Chimenti Konrad Urbanek Marcello Rota Ezio Musso Annarosa Leri Jan Kajstura Piero Anversa