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Experimental and Computational Approaches to Direct Cell Reprogramming: Recent Advancement and Future Challenges
Open AccessArticle

Isoform Specific Effects of Mef2C during Direct Cardiac Reprogramming

by Li Wang 1,2,†, Peisen Huang 1,2,3,4,†, David Near 1,2, Karan Ravi 1,2, Yangxi Xu 1,2, Jiandong Liu 1,2 and Li Qian 1,2,*
McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou 510080, China
Author to whom correspondence should be addressed.
These authors contributed equally to this article.
Cells 2020, 9(2), 268; (registering DOI)
Received: 16 September 2019 / Revised: 13 January 2020 / Accepted: 20 January 2020 / Published: 22 January 2020
Direct conversion of cardiac fibroblasts into induced cardiomyocytes (iCMs) by forced expression of defined factors holds great potential for regenerative medicine by offering an alternative strategy for treatment of heart disease. Successful iCM conversion can be achieved by minimally using three transcription factors, Mef2c (M), Gata4(G), and Tbx5 (T). Despite increasing interest in iCM mechanistic studies using MGT(polycistronic construct with optimal expression of M,G and T), the reprogramming efficiency varies among different laboratories. Two main Mef2c isoforms (isoform2, Mi2 and isoform4, Mi4) are present in heart and are used separately by different labs, for iCM reprogramming. It is currently unknown if differently spliced isoform of Mef2c contributes to varied reprogramming efficiency. Here, we used Mi2 and Mi4 together with Gata4 and Tbx5 in separate vectors or polycistronic vector, to convert fibroblasts to iCMs. We found that Mi2 can induce higher reprogramming efficiency than Mi4 in MEFs. Addition of Hand2 to MGT retroviral cocktail or polycistronic Mi2-GT retroviruses further enhanced the iCM conversion. Overall, this study demonstrated the isoform specific effects of Mef2c, during iCM reprogramming, clarified some discrepancy about varied efficiency among labs and might lead to future research into the role of alternative splicing and the consequent variants in cell fate determination. View Full-Text
Keywords: fibroblasts; Mef2C protein; isoform; cardiac myocytes; reprogramming fibroblasts; Mef2C protein; isoform; cardiac myocytes; reprogramming
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Wang, L.; Huang, P.; Near, D.; Ravi, K.; Xu, Y.; Liu, J.; Qian, L. Isoform Specific Effects of Mef2C during Direct Cardiac Reprogramming. Cells 2020, 9, 268.

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