Research ArticleRegenerative Medicine

A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice

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Science Translational Medicine  18 Mar 2015:
Vol. 7, Issue 279, pp. 279ra38
DOI: 10.1126/scitranslmed.3010841

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Heart regeneration: Small cues from development

With limited ability to repair itself after injury, the mature heart may need to look to development for some lessons. By reactivating pathways that are present during mammalian development, it may be possible to encourage cardiac regeneration. In mice, Tian et al. found that the microRNA cluster mir302-367 stimulates cardiomyocyte proliferation during early heart development by inhibiting the Hippo pathway. Transient treatment with miR302-367 mimics promoted cardiac regeneration in mice after myocardial infarction, suggesting that such small RNAs can be harnessed therapeutically to repair the adult heart.

Abstract

In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. We show that the microRNA cluster miR302-367 is important for cardiomyocyte proliferation during development and is sufficient to induce cardiomyocyte proliferation in the adult and promote cardiac regeneration. In mice, loss of miR302-367 led to decreased cardiomyocyte proliferation during development. In contrast, increased miR302-367 expression led to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. Postnatal reexpression of miR302-367 reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction. However, long-term expression of miR302-367 induced cardiomyocyte dedifferentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes is not desirable. This limitation can be overcome by transient systemic application of miR302-367 mimics, leading to increased cardiomyocyte proliferation and mass, decreased fibrosis, and improved function after injury. Our data demonstrate the ability of microRNA-based therapeutic approaches to promote mammalian cardiac repair and regeneration through the transient activation of cardiomyocyte proliferation.

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