Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.
Bibliographical noteFunding Information:
We thank M. Schwarz and P. Schwarz for administrative support. We are grateful to Thai B. Nguyen, Yun Xia, Chris Benner, Daiji Okamura, Manching Ku, James Kasubowski, Merce Marti, and the Waitt Advanced Biophotonicis Core at the Salk Institute for excellent technical assistance and useful discussions. We would also like to thank Louise C. Laurent and Robert Morey for their help with bioinformatics analyses. A.A. was partially supported by the Ipsen Foundation. L.K. was partially supported by a training grant from the California Institute for Regenerative Medicine. I.S.M. was partially supported by a Nomis Foundation postdoctoral fellowship. Work in the lab of J.Y. was supported by National Institute of General Medical Sciences (8 P41 GM103533) and UCLA/NHLBI Proteomics Centers (HHSN268201000035C). Work in the laboratory of J.C.I.B. was supported by grants from MINECO PLE2009-0100 (CMRB), the NHLBI (U01 HL107442-04), the G. Harold and Leila Y. Mathers Charitable Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002) (Salk Institute).
©2014 Elsevier Inc.
ASJC Scopus subject areas
- Molecular Medicine
- Cell Biology