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

被引:14
|
作者
Bektik, Emre [1 ,2 ,3 ]
Dennis, Adrienne [1 ]
Pawlowski, Gary [1 ]
Zhou, Chen [1 ]
Maleski, Danielle [1 ]
Takahashi, Satoru [2 ,3 ]
Laurita, Kenneth R. [1 ]
Deschenes, Isabelle [1 ]
Fu, Ji-Dong [1 ]
机构
[1] Case Western Reserve Univ, Heart & Vasc Res Ctr, Dept Med, MetroHlth Campus, Cleveland, OH 44109 USA
[2] Univ Tsukuba, Sch Integrat & Global Majors, PhD Program Human Biol, Tsukuba, Ibaraki 3058577, Japan
[3] Univ Tsukuba, Dept Anat & Embryol, Fac Med, Tsukuba, Ibaraki 3058577, Japan
基金
日本学术振兴会;
关键词
induced cardiomyocyte; epigenetic reprogramming; cell division; cell-cycle synchronization; cell-cycle exit; HUMAN FIBROBLASTS; FUNCTIONAL CARDIOMYOCYTES; CARDIAC FIBROBLASTS; DEFINED FACTORS; IN-VITRO; EXPRESSION; EFFICIENCY; CONVERSION; SIGNATURES; QUALITY;
D O I
10.3390/ijms19051364
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页数:14
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