Redirecting cardiac growth mechanisms for therapeutic regeneration

Abstract

Heart failure is a major source of morbidity and mortality. Replacing lost myocardium with new tissue is a major goal of regenerative medicine. Unlike adult mammals, zebrafish and neonatal mice are capable of heart regeneration following cardiac injury. In both contexts, the regenerative program echoes molecular and cellular events that occur during cardiac development and morphogenesis, notably muscle creation through division of cardiomyocytes. Based on studies over the past decade, it is now accepted that the adult mammalian heart undergoes a low grade of cardiomyocyte turnover. Recent data suggest that this cardiomyocyte turnover can be augmented in the adult mammalian heart by redeployment of developmental factors. These findings and others suggest that stimulating endogenous regenerative responses can emerge as a therapeutic strategy for human cardiovascular disease.

Figure 1. Modes of cardiomyocyte growth.

(A) During cardiac development, cardiac growth occurs through addition of new cardiomyocytes via progenitor cell differentiation (top) followed by hyperplastic growth (bottom). Undifferentiated progenitor cells give rise to cardiac progenitors at the heart tube stage, followed by hyperplastic proliferation of cardiomyocytes during the remainder of development. (B) In contrast, the adult mammalian heart grows predominantly by either physiologic hypertrophy (top) or pathologic hypertrophy (bottom). With physiologic hypertrophy, the heart uniformly enlarges without organ fibrosis. Pathologic hypertrophy occurs after injury and is marked by fibrosis and heterogeneous cellular hypertrophy.

Figure 2. Postnatal cardiomyocyte cycling in the adult mammalian heart and challenges in assessing cardiac regeneration.

In the adult mammalian heart, the majority of cardiomyocytes are quiescent and do not cycle. Rare cardiomyocytes that do cycle preferentially undergo endoreplication rather than complete mitosis. This creates challenges in assessing mammalian heart regeneration. Indices of cardiomyocyte cycling can mark true regeneration through hyperplastic growth but are more likely to mark cardiomyocytes that undergo endoreplication without making new muscle. Similarly, increased ventricular function is associated with regeneration following the creation of new muscle, but may be increased following endoreplication as well.