Transient induction of actin cytoskeletal remodeling associated with dedifferentiation,proliferation,and redifferentiation stimulates cardiac regeneration  

作　　者：Wenbin Fu Qiao Liao Yu Shi Wujian Liu Hongmei Ren Chunmei Xu Chunyu Zeng 

机构地区：[1]Department of Cardiology,Daping Hospital,the Third Military Medical University(Army Medical University),Chongqing 400042,China [2]Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research,Ministry of Education of China,Chongqing 400042,China [3]Chongqing Key Laboratory for Hypertension Research,Chongqing Cardiovascular Clinical Research Center,Chongqing Institute of Cardiology,Chongqing 400042,China [4]State Key Laboratory of Trauma,Burns and Combined Injury,Daping Hospital,the Third Military Medical University,Chongqing 400042,China [5]Cardiovascular Research Center,Chongqing College,University of Chinese Academy of Sciences,Chongqing 400042,China [6]State Key Laboratory of Trauma and Chemical Poisoning,Chongqing 400042,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2537-2553,共17页药学学报（英文版）

基　　金：supported by the grant to Chunyu Zeng from the National Key R&D Program of China(2022YFA1104500);the National Natural Science Foundation of China(82200307);the grant to Chunyu Zeng from the National Natural Science Foundation of China(81930008).

摘　　要：The formation of new and functional cardiomyocytes requires a 3-step process:dedifferentiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferentiation,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 dedifferentiation,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 sustained 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 remodeling 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.

关 键 词：Single cell analysis Actin remodeling Tmsb4x Tmsb10 Dmd Ctnna3 Myocardial infarction Cardiomyocytes proliferation Cardiac regeneration Genetic therapy 

分 类 号：R575[医药卫生—消化系统]