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

Yuanbiao Zhao, Pilar Londono, Yingqiong Cao, Emily J. Sharpe, Catherine Proenza, Rebecca O’Rourke, Kenneth L. Jones, Mark Y. Jeong, Lori A. Walker, Peter M. Buttrick, Timothy A. McKinsey and Kunhua Song ()
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Yuanbiao Zhao: University of Colorado School of Medicine
Pilar Londono: University of Colorado School of Medicine
Yingqiong Cao: University of Colorado School of Medicine
Emily J. Sharpe: University of Colorado School of Medicine
Catherine Proenza: University of Colorado School of Medicine
Rebecca O’Rourke: University of Colorado School of Medicine
Kenneth L. Jones: University of Colorado School of Medicine
Mark Y. Jeong: University of Colorado School of Medicine
Lori A. Walker: University of Colorado School of Medicine
Peter M. Buttrick: University of Colorado School of Medicine
Timothy A. McKinsey: University of Colorado School of Medicine
Kunhua Song: University of Colorado School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9243

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