Meis1 regulates postnatal cardiomyocyte cell cycle arrest

• Published in: Nature (London) Vol. 497; no. 7448; pp. 249 - 253
• Main Authors: Mahmoud, Ahmed I., Kocabas, Fatih, Muralidhar, Shalini A., Kimura, Wataru, Koura, Ahmed S., Thet, Suwannee, Porrello, Enzo R., Sadek, Hesham A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.05.2013; Nature Publishing Group
• Subjects: 631/443/592/2725; 631/80; Alleles; Animals; Animals, Newborn; Apoptosis; Cardiomyocytes; Cell cycle; Cell Cycle Checkpoints; Cell Proliferation; Cellular control mechanisms; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; Gene expression; Heart; Heart - anatomy & histology; Heart - physiology; Heart attacks; Heart cells; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Kinases; letter; Male; Mice; multidisciplinary; Myeloid Ecotropic Viral Integration Site 1 Protein; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Neoplasm Proteins - deficiency; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Proteins; Regeneration; Science; Transcriptional Activation; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12054

The neonatal heart has a high regenerative capacity that is lost in adult life; the transcription factor Meis1 has been identified as a relevant proliferative switch for this transition, providing a potential therapeutic target for adult heart regeneration. Heart cells that keep on growing Adult mammalian hearts cannot regenerate after injury, but neonatal mouse hearts can regenerate through cardiomyocyte proliferation until postnatal day 7, when the cells exit the cell cycle. Hesham Sadek and colleagues now provide insight into the mechanisms behind this transition. They show that the transcription factor Meis1 regulates the cardiomyocyte cell cycle, and that deletion of the Meis1 gene in cardiomyocytes extends their postnatal proliferative window beyond 7 days. Conversely, overexpression of Meis1 inhibits neonatal mouse heart regeneration. These results demonstrate that the early postnatal cardiac regenerative window may hold the key to the potential of the adult mammalian heart to regenerate, and that Meis1 is a potential therapeutic target. The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation 1 , 2 . 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 3 , 4 . 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 re-activation 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.