首页|Transient induction of actin cytoskeletal remodeling associated with dedifferentiation,proliferation,and redifferentiation stimulates cardiac regeneration
Transient induction of actin cytoskeletal remodeling associated with dedifferentiation,proliferation,and redifferentiation stimulates cardiac regeneration
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The formation of new and functional cardiomyocytes requires a 3-step process:dediffer-entiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferen-tiation,proliferation,and redifferentiation remain unknown.In our study,a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive(PCM1+)cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction(MI)on postnatal Day 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentia-tion,proliferation,and redifferentiation of cardiomyocytes after injury.We identified four top actin-remodeling regulators,namely Tmsb4x,Tmsb10,Dmd,and Ctnna3,which we collectively referred to as 2D2P.Transiently expressed changes of 2D2P,using a polycistronic non-integrating lentivirus driven by Tnnt2(cardiac-specific troponin T)promoters(Tnnt2-2D2P-NIL),efficiently induced transiently proliferative activation and actin remodeling in postnatal Day 7 cardiomyocytes and adult hearts.Furthermore,the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sus-tained improvement in cardiac function without ventricular dilatation,thickened septum,or fatal arrhythmia for at least 4 months.In conclusion,this study highlights the importance of actin remo-deling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.
Single cell analysisActin remodelingTmsb4xTmsb10DmdCtnna3Myocardial infarctionCardiomyocytes proliferationCardiac regenerationGenetic therapy
Department of Cardiology,Doping Hospital,the Third Military Medical University(Army Medical University),Chongqing 400042,China
Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research,Ministry of Education of China,Chongqing 400042,China
Chongqing Key Laboratory for Hypertension Research,Chongqing Cardiovascular Clinical Research Center,Chongqing Institute of Cardiology,Chongqing 400042,China
State Key Laboratory of Trauma,Burns and Combined Injury,Doping Hospital,the Third Military M
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National Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China
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