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Int. J. Mol. Sci. 2018, 19(5), 1364; https://doi.org/10.3390/ijms19051364

S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit

1
Department of Medicine, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109, USA
2
Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8577, Japan
3
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8577, Japan
*
Author to whom correspondence should be addressed.
Received: 16 March 2018 / Revised: 27 April 2018 / Accepted: 28 April 2018 / Published: 4 May 2018
(This article belongs to the Special Issue Cell Reprogramming)
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Abstract

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds a great promise for regenerative medicine and has been studied in several major directions. However, cell-cycle regulation, a fundamental biological process, has not been investigated during iCM-reprogramming. Here, our time-lapse imaging on iCMs, reprogrammed by Gata4, Mef2c, and Tbx5 (GMT) monocistronic retroviruses, revealed that iCM-reprogramming was majorly initiated at late-G1- or S-phase and nearly half of GMT-reprogrammed iCMs divided soon after reprogramming. iCMs exited cell cycle along the process of reprogramming with decreased percentage of 5-ethynyl-20-deoxyuridine (EdU)+/α-myosin heavy chain (αMHC)-GFP+ cells. S-phase synchronization post-GMT-infection could enhance cell-cycle exit of reprogrammed iCMs and yield more GFPhigh iCMs, which achieved an advanced reprogramming with more expression of cardiac genes than GFPlow cells. However, S-phase synchronization did not enhance the reprogramming with a polycistronic-viral vector, in which cell-cycle exit had been accelerated. In conclusion, post-infection synchronization of S-phase facilitated the early progression of GMT-reprogramming through a mechanism of enhanced cell-cycle exit. View Full-Text
Keywords: induced cardiomyocyte; epigenetic reprogramming; cell division; cell-cycle synchronization; cell-cycle exit induced cardiomyocyte; epigenetic reprogramming; cell division; cell-cycle synchronization; cell-cycle exit
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bektik, E.; Dennis, A.; Pawlowski, G.; Zhou, C.; Maleski, D.; Takahashi, S.; Laurita, K.R.; Deschênes, I.; Fu, J.-D. S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit. Int. J. Mol. Sci. 2018, 19, 1364.

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