A Microrna Pathway That Promotes Cardiomyocyte Proliferation And Cardiac Regeneration By Inhibiting Hippo Signaling

In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. While evidence exists for a low level of cardiomyocyte proliferation in the adult heart, it remains unclear whether increasing the rate could be used to therapeutically promote cardiac regeneration. In this study, 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. Loss of miR302-367 leads to decreased cardiomyocyte proliferation during development. In contrast, increased miR302-367 expression leads to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. Postnatal re-expression of miR302-367 leads to reactivation of the cell cycle in cardiomyocytes resulting in reduced scar formation after infarction. However, long-term expression of miR302-367 leads to cardiomyocyte de-differentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes is not desirable. Importantly, 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 cardiac repair and regeneration through the transient activation of cardiomyocyte proliferation.