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Chemical Enhancement of In Vitro and In Vivo Direct Cardiac Reprogramming.

  • Author(s): Mohamed, Tamer MA
  • Stone, Nicole R
  • Berry, Emily C
  • Radzinsky, Ethan
  • Huang, Yu
  • Pratt, Karishma
  • Ang, Yen-Sin
  • Yu, Pengzhi
  • Wang, Haixia
  • Tang, Shibing
  • Magnitsky, Sergey
  • Ding, Sheng
  • Ivey, Kathryn N
  • Srivastava, Deepak
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340593/
No data is associated with this publication.
Abstract

Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells in situ represents a promising strategy for cardiac regeneration. A combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), can convert fibroblasts into induced cardiomyocyte-like cells, albeit with low efficiency in vitro.We screened 5500 compounds in primary cardiac fibroblasts to identify the pathways that can be modulated to enhance cardiomyocyte reprogramming.We found that a combination of the transforming growth factor-β inhibitor SB431542 and the WNT inhibitor XAV939 increased reprogramming efficiency 8-fold when added to GMT-overexpressing cardiac fibroblasts. The small molecules also enhanced the speed and quality of cell conversion; we observed beating cells as early as 1 week after reprogramming compared with 6 to 8 weeks with GMT alone. In vivo, mice exposed to GMT, SB431542, and XAV939 for 2 weeks after myocardial infarction showed significantly improved reprogramming and cardiac function compared with those exposed to only GMT. Human cardiac reprogramming was similarly enhanced on transforming growth factor-β and WNT inhibition and was achieved most efficiently with GMT plus myocardin.Transforming growth factor-β and WNT inhibitors jointly enhance GMT-induced direct cardiac reprogramming from cardiac fibroblasts in vitro and in vivo and provide a more robust platform for cardiac regeneration.

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