Cardiac stem cell therapy and the promise of heart regeneration

Abstract

Stem cell therapy for cardiac disease is an exciting but highly controversial research area. Strategies such as cell transplantation and reprogramming have demonstrated both intriguing and sobering results. Yet as clinical trials proceed, our incomplete understanding of stem cell behavior is made evident by numerous unresolved matters, such as the mechanisms of cardiomyocyte turnover or the optimal therapeutic strategies to achieve clinical efficacy. In this Perspective, we consider how cardiac stem cell biology has led us into clinical trials, and we suggest that achieving true cardiac regeneration in patients may ultimately require resolution of critical controversies in experimental cardiac regeneration.

Figure 1. Mammalian Cardiogenesis during Aging

Multiple lines of evidence exist for the refreshment of cardiomyocytes during aging in mammals, with two predominant mechanisms proposed to explain the source of new cardiomyocytes during aging: (1) progenitor cells that give rise to new cardiomyocytes exist in the heart throughout life or (2) mature cardiomyocytes undergo partial dedifferentiation, reenter the cell cycle, and proliferate into new cardiomyocytes. Results from the majority of investigators suggest that this turnover rate occurs at a low level (approximately 1% per year in young adults) and declines even further with age.

Figure 2. Proposed Mechanisms for Generation of New Cardiomyocytes after Injury

Four potential mechanisms of the heart's response to injury may lead to a regenerative response (clockwise from top): (1) paracrine factors are released by noncardiomyocyte cells to promote the proliferation of existing cardiomyocytes; (2) progenitor cells activate, proliferate, and undergo differentiation into new cardiomyocytes; (3) mature cardiomyocytes undergo dedifferentiation, reenter the cell cycle, and proliferate into new cardiomyocytes; or (4) injury results in activation of the epicardium, leading to growth of new blood vessels and/or proliferation of new cardiomyocytes.

Figure 3. Approaches to Cardiac Regeneration after Injury

Multiple strategies are under investigation to promote cardiac regeneration in diseased hearts (clockwise from top): (1) cell therapy with cultured cells injected into the myocardium or coronary arteries is in clinical trials, with hopes that these cells may become functional cardiomyocytes; (2) tissue engineering approaches that combine cells with biomaterials to create functional tissue in vitro for transplantation into the heart; (3) reprogramming noncardiomyocytes into cardiomyocytes in situ may be accomplished with viruses, small molecules, or microRNAs; and (4) small molecules such as growth factors or microRNAs that are delivered to promote wound healing via cardiomyocyte proliferation or angiogenesis.