title: A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice.
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.
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. ying.tian@temple.edu emorrise@mail.med.upenn.edu.
authors: Ying
authors: Y
authors: Tian
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Ying
authors: Y
authors: Liu
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Tao
authors: T
authors: Wang
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors: Ning
authors: N
authors: Zhou
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Jun
authors: J
authors: Kong
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Li
authors: L
authors: Chen
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Melinda
authors: M
authors: Snitow
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Michael
authors: M
authors: Morley
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Deqiang
authors: D
authors: Li
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors: Nataliya
authors: N
authors: Petrenko
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Su
authors: S
authors: Zhou
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Minmin
authors: M
authors: Lu
authors: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors: Erhe
authors: E
authors: Gao
authors: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors: Walter J
authors: WJ
authors: Koch
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Kathleen M
authors: KM
authors: Stewart
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA19104, USA. Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. ying.tian@temple.edu emorrise@mail.med.upenn.edu.
authors: Edward E
authors: EE
authors: Morrisey
mesh_terms: D000483:Alleles; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D005434:Flow Cytometry; D057809:HEK293 Cells; D006321:Heart / Q000502:physiology; D000090683:Hippo Signaling Pathway; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction
chemical_list: D008055:Lipids; C558265:MIRN302 microRNA, mouse; C000598715:MIRN367 microRNA, mouse; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases