An Unexpected Switch Regulation of Cardiomyocyte Proliferation by the Homeobox Gene Meis1

The mammalian heart has a limited capacity for regeneration after damage. In contrast, teleost fish and urodelian amphibians readily regenerate even large cardiac defects. One of the central differences between species capable and incapable of efficient heart regeneration is the ability to reinitiate cardiomyocyte proliferation. The importance of cardiomyocyte proliferation for heart regeneration is underscored by the finding that fetal and neonatal mouse hearts efficiently regenerate until efficient proliferation of cardiomyocytes ends during the first week after birth.1,2 In a recent article in Nature , Mahmoud et al3 now reported that constitutive and inducible cardiomyocyte–specific deletion of the homeobox gene Meis1 lifts the ban on cardiomyocyte proliferation in adult hearts of mice. Meis1 deficiency increases cardiomyocyte numbers and heart/body weight ratio while maintaining cardiomyocyte size and heart function. Overexpression of Meis1 , however, blocks cardiomyocyte proliferation and heart regeneration after myocardial infarction in newborn mice, suggesting that Meis1 acts as a critical driver of cell cycle arrest in the postnatal myocardium. The traditional view of the adult heart as an essentially postmitotic organ has changed substantially in the past few years. It is now widely acknowledged that the heart has the ability to undergo a certain degree of renewal, although the extent and the cellular origin(s) of renewal are still debated. Newly generated cardiomyocytes have been claimed to be primarily derived from resident cardiac stem cells4 or bone marrow–derived stem cells.5 More recently, the older idea of low-level proliferation of preexisting cardiomyocytes in the mammalian heart has gained new appeal because of the use of novel genetic fate-mapping and isotope labeling technologies.6 Further support for heart regeneration from pre-existing cardiomyocytes comes from recent observations in teleost fish and urodelians.7–9 New cardiomyocytes might originate from fully differentiated mononucleated cardiomyocytes or from cardiomyocytes that …