Enhanced Generation of Induced Cardiomyocytes Using a Small‐Molecule Cocktail to Overcome Barriers to Cardiac Cellular Reprogramming
Open Access
- 16 June 2020
- journal article
- research article
- Published by Wolters Kluwer Health in Journal of the American Heart Association
- Vol. 9 (12), e015686
- https://doi.org/10.1161/jaha.119.015686
Abstract
Background Given known inefficiencies in reprogramming of fibroblasts into mature induced cardiomyocytes (iCMs), we sought to identify small molecules that would overcome these barriers to cardiac cell transdifferentiation. Methods and Results We screened alternative combinations of compounds known to impact cell reprogramming using morphologic and functional cell differentiation assays in vitro. After screening 6 putative reprogramming factors, we found that a combination of the histone deacetylase inhibitor sodium butyrate, the WNT inhibitor ICG‐001, and the cardiac growth regulator retinoic acid (RA) maximally enhanced iCM generation from primary rat cardiac fibroblasts when combined with administration of the cardiodifferentiating transcription factors Gata4, Mef2C, and Tbx5 (GMT) compared with GMT administration alone (23±1.5% versus 3.3±0.2%; PP<0.0001). Rat and human iCMs also more frequently demonstrated spontaneous beating in coculture with neonatal cardiomyocytes with the addition of sodium butyrate, ICG‐001, and RA to transcription factor cocktails compared with transcription factor treatment alone. Conclusions The combined administration of histone deacetylase and WNT inhibitors with RA enhances rat and human iCM generation induced by transcription factor administration alone. These findings suggest opportunities for improved translational approaches for cardiac regeneration.Keywords
This publication has 54 references indexed in Scilit:
- Transcription Factors MYOCD, SRF, Mesp1 and SMARCD3 Enhance the Cardio-Inducing Effect of GATA4, TBX5, and MEF2C during Direct Cellular ReprogrammingPLOS ONE, 2013
- In Vivo Cardiac Cellular Reprogramming Efficacy Is Enhanced by Angiogenic Preconditioning of the Infarcted Myocardium With Vascular Endothelial Growth FactorJournal of the American Heart Association, 2012
- MicroRNA-Mediated In Vitro and In Vivo Direct Reprogramming of Cardiac Fibroblasts to CardiomyocytesCirculation Research, 2012
- Heart repair by reprogramming non-myocytes with cardiac transcription factorsNature, 2012
- In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytesNature, 2012
- Butyrate Promotes Induced Pluripotent Stem Cell GenerationJournal of Biological Chemistry, 2010
- Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined FactorsCell, 2010
- Endogenous retinoic acid regulates cardiac progenitor differentiationProceedings of the National Academy of Sciences, 2010
- iPS Cells Reprogrammed From Human Mesenchymal-Like Stem/Progenitor Cells of Dental Tissue OriginStem Cells and Development, 2010
- Histone Deacetylase Inhibition Elicits an Evolutionarily Conserved Self-Renewal Program in Embryonic Stem CellsCell Stem Cell, 2009