The data reviewed here indicate that constitutive expression of cyclin D2 is sufficient to promote cardiomyocyte cell cycle activity in postnatal hearts and that this cell cycle activity results in myocardial regeneration and functional recovery following injury. To date, a number of gene products have been shown to promote structural and/or functional recovery in injured hearts; for example, deletion of the p38 MAP kinase gene results in FGF1-inducible cell cycle progression in postnatal cardiomyocytes in vitro and in vivo [
4]. Transient pharmacologic inhibition of p38 MAP kinase, in combination with FGF1 treatment, resulted in improved cardiac structure and function at 3 months postinfarction in adult rats [
5]; however, the degree to which proproliferation, antiapoptotic and/or antihypertrophic activities contributed the observed improvement is not clear. Transgenic mice expressing cyclin A2 (which can regulate both restriction point transit and mitosis entry) exhibited enhanced cardiomyocyte cell cycle activity in early postnatal life, but not in adults [
2]. Viral delivery of cyclin A2 in infarcted rat hearts had a positive impact on cardiac structure and function [
24], although the cell type responsible for the observed improvement was not clear. As reported elsewhere, genetic deletion of c-kit renders postnatal cardiomyocytes able to reenter the cell cycle following injury [
8]. Finally, cardiomyocyte-restricted deletion of the RB gene, in the presence of global deletion of p130 (another member of the RB gene family), gave rise to cardiomyocyte hypertrophy and hyperplasia in postnatal hearts [
9].
These are but a few examples of genetic pathways that can be exploited to induce cell cycle activity in postnatal cardiomyocytes. However, there remain a number of issues that must be experimentally addressed to validate these genes as potential targets to induce regenerative growth; for example, most studies utilized genetic manipulations that occurred prior to cardiomyocyte terminal differentiation. Hence, it is possible that similar manipulation in adult cardiomyocytes might not have the same result. This is likely not the case with targets aimed at modulating restriction point transit, as viral delivery of a cyclin D1 molecule carrying a nuclear localization sequence, in combination with CDK4, was sufficient to induce cardiomyocyte cell cycle activity in adult rat hearts [
22]. Similarly, as indicated earlier, pharmacologic modulation of p38 MAP kinase and FGF1 resulted in cell cycle progression in adult hearts. Perhaps even more important is to determine if the genetic pathways in question are also operative in human cardiomyocytes. The ability to isolate and engraft cardiomyogenic precursors from human embryonic stem cells [
25] as well as other cardiomyogenic precursors will greatly facilitate such analyses. Finally, once manipulation of a given genetic pathway is validated as a target for inducing regenerative growth, it would be highly desirable to develop molecules that mimic the genetic modification, thereby obviating the need for gene transfer-based interventions.