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Nat Commun. 2015 Sep 10;6:8243. doi: 10.1038/ncomms9243.

High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling.

Author information

1
Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, 12700 E. 19th Avenue, B139, Aurora, Colorado 80045, USA.
2
Department of Physiology and Biophysics, University of Colorado School of Medicine, 12800 E. 19th Avenue, Aurora, Colorado 80045, USA.
3
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, 12801 E. 17th Avenue, Aurora, Colorado 80045, USA.
4
Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado School of Medicine, 12700 E. 19th Avenue, B139, Aurora, Colorado 80045, USA.

Abstract

Direct reprogramming of fibroblasts into cardiomyocytes by forced expression of cardiomyogenic factors, GMT (GATA4, Mef2C, Tbx5) or GHMT (GATA4, Hand2, Mef2C, Tbx5), has recently been demonstrated, suggesting a novel therapeutic strategy for cardiac repair. However, current approaches are inefficient. Here we demonstrate that pro-fibrotic signalling potently antagonizes cardiac reprogramming. Remarkably, inhibition of pro-fibrotic signalling using small molecules that target the transforming growth factor-β or Rho-associated kinase pathways converts embryonic fibroblasts into functional cardiomyocyte-like cells, with the efficiency up to 60%. Conversely, overactivation of these pro-fibrotic signalling networks attenuates cardiac reprogramming. Furthermore, inhibition of pro-fibrotic signalling dramatically enhances the kinetics of cardiac reprogramming, with spontaneously contracting cardiomyocytes emerging in less than 2 weeks, as opposed to 4 weeks with GHMT alone. These findings provide new insights into the molecular mechanisms underlying cardiac conversion of fibroblasts and would enhance efforts to generate cardiomyocytes for clinical applications.

PMID:
26354680
PMCID:
PMC4579788
DOI:
10.1038/ncomms9243
[Indexed for MEDLINE]
Free PMC Article

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