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Open AccessArticle

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