Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes.
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.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
Huanyu
H
Zhou
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
Matthew E
ME
Dickson
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390-9066.
Min Soo
MS
Kim
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
Rhonda
R
Bassel-Duby
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Eric.Olson@utsouthwestern.edu.
Eric N
EN
Olson
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium
cardiogenesis; cardiomyopathy; heart; regeneration; transdifferentiation