Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/ijms19051364
Keywords
induced cardiomyocyte; epigenetic reprogramming; cell division; cell-cycle synchronization; cell-cycle exit
Funding
- MetroHealth System
- American Heart Association [13SDG14580035, NIH-1R01HL139006, NIH-1R01HL124245, NIH-1R01HL132520]
- Program for Leading Graduate Schools of the Japan Society for the Promotion of Science (JSPS)
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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)(+)/-myosin heavy chain (MHC)-GFP(+) cells. S-phase synchronization post-GMT-infection could enhance cell-cycle exit of reprogrammed iCMs and yield more GFP(high) iCMs, which achieved an advanced reprogramming with more expression of cardiac genes than GFP(low) 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.
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