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Author(s): Ngoc Uyen Nhi Nguyen [sup.1] , Diana C. Canseco [sup.1] , Feng Xiao [sup.1] , Yuji Nakada [sup.1] , Shujuan Li [sup.1] , Nicholas T. Lam [sup.1] , Shalini [...], A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes.sup.1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest.sup.3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes. Hoxb13 acts as a cofactor of Meis1 in regulating cardiomyocyte maturation and cell cycle, and knockout of both proteins enables regeneration of postnatal cardiac tissue in a mouse model of heart injury.

Author(s): Yuji Nakada [1]; Diana C. Canseco [1]; SuWannee Thet [1]; Salim Abdisalaam [2]; Aroumougame Asaithamby [2]; Celio X. Santos [3]; Ajay M. Shah [3]; Hua Zhang [4]; James E. [...]

It was recently reported that new cardiomyocytes in the adult heart are derived from pre-existing cardiomyocytes (3-5), although the identity of cycling cardiomyoctes, and the mechanism of their proliferative competency [...], Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts (1,2), mediated primarily by proliferation of pre-existing cardiomyocytes (3-5). However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers (6). In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function (7-10). Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1α is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific a myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.