Defining the Limit of Embryonic Heart Regeneration.

C ardiomyocyte replacement has been the focus of intense research because of the significant burden of heart failure. Although the adult mammalian heart is nonregenera-tive, recent studies have demonstrated that it retains a modest degree of cardiomyocyte turnover throughout life, mediated primarily by the proliferation of preexisting cardiomyo-cytes. In contrast to the adult heart, the neonatal mamma-lian heart possesses a remarkable regenerative ability in the first few days of life mediated by the proliferation of preex-isting cardiomyocytes, after which cardiomyocytes permanently exit the cell cycle, and the regenerative ability of the heart is lost. 3,4 Importantly, the embryonic mammalian heart also possesses a remarkable regenerative ability. Embryonic cardiomyocyte replacement studies were previously reported by the Cox 5 and Torres 6 groups. The Cox group showed that compensatory growth of cardiomyocytes occurred following cardiomyocyte ablation with the use of a holocytochrome c synthase–deficient model, whereas the Torres group demonstrated that cell competition promotes the silent exchange of cardiomyocytes without heart failure. Although these studies demonstrated that the fetal and early postnatal myocardium is capable of significant cardiomyocyte turnover and renewal, it remained unclear whether there is a limit to the regenerative capacity of the mammalian myocardium. In this issue of Circulation, Sturzu and colleagues 7 rigorously addressed the extent of embryonic heart regenera-tion following acute cardiomyocyte loss. They generated a genetic ablation model of cardiomyocytes in mouse embryonic hearts using a diphtheria toxin–based ablation system. They successfully eliminated cardiac progenitor cells or immature cardiomyocytes at various levels in the mouse embryonic heart. Nkx2.5-Cre or αMHC-Cre lines were crossed with a ROSA26 eGFP-DTA line, thereby resulting in ablation of Cre-expressing cells. The embryonic stem cells established from these Nkx2.5-Cre and αMHC-Cre blastocysts were injected into wild-type blastocysts to generate cardiac progenitor cell– or cardiomyocyte–ablated chimeric embryonic hearts, respectively. Taking advantage of blastocyst chimerism, chimeric embryos demonstrated successful ablation of cardiomyocytes to various degrees, from 0% to 95%. Intriguingly, the embry-onic hearts were able to recover from substantial cardiomyo-cyte loss of up to 60% by using either cardiac progenitor cell or cardiomyocyte ablation, and they showed no signs of cardiac atrophy, hypertrophy, or dysfunction. Of note, previous studies of the genetic ablation of zebrafish cardiomyocytes showed a similar limit of myocardial regeneration, where ablation of up to 60% of cardiomyocytes was compatible with regeneration. 8 Although no comparable detailed quantification studies have been performed to assess the precise extent of neonatal heart regeneration, …