Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes

Huanyu Zhou, Matthew E. Dickson, Min Soo Kim, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Conversion of fibroblasts to functional cardiomyocytes represents a potential approach for restoring cardiac function after myocardial injury, but the technique thus far has been slow and inefficient. To improve the efficiency of reprogramming fibroblasts to cardiac-like myocytes (iCMs) by cardiac transcription factors [Gata4, Hand2, Mef2c, and Tbx5 (GHMT)], we screened 192 protein kinases and discovered that Akt/protein kinase B dramatically accelerates and amplifies this process in three different types of fibroblasts (mouse embryo, adult cardiac, and tail tip). Approximately 50% of reprogrammed mouse embryo fibroblasts displayed spontaneous beating after 3 wk of induction by Akt plus GHMT. Furthermore, addition of Akt1 to GHMT evoked a more mature cardiac phenotype for iCMs, as seen by enhanced polynucleation, cellular hypertrophy, gene expression, and metabolic reprogramming. Insulin-like growth factor 1 (IGF1) and phosphoinositol 3-kinase (PI3K) acted upstream of Akt whereas the mitochondrial target of rapamycin complex 1 (mTORC1) and forkhead box o3 (Foxo3a) acted downstream of Akt to influence fibroblast-to-cardiomyocyte reprogramming. These findings provide insights into the molecular basis of cardiac reprogramming and represent an important step toward further application of this technique.

Original languageEnglish (US)
Pages (from-to)11864-11869
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number38
DOIs
StatePublished - Sep 22 2015

Keywords

  • Cardiogenesis
  • Cardiomyopathy
  • Heart
  • Regeneration
  • Transdifferentiation

ASJC Scopus subject areas

  • General

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