Meis1 regulates postnatal cardiomyocyte cell cycle arrest

The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation (Porrello et al, Science 331:1078- 1080, 2011; Proc Natl Acad Sci U S A 110:187-92, 2013). However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown (Paige et al, Cell 151:221-232, 2012; Wamstad et al, Cell 151: 206-220, 2012). Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes and for reactivation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16, and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.