title: Reprogramming-derived gene cocktail increases cardiomyocyte proliferation for heart regeneration.
abstract: Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regulation of several mitosis-related genes at this stage of reprogramming. Several candidate genes were selected and tested for their ability to induce CM proliferation. Delivering a cocktail of three genes, FoxM1, Id1, and Jnk3-shRNA (FIJs), induced CMs to re-enter the cell cycle and complete mitosis and cytokinesis in vitro More importantly, this gene cocktail increased CM proliferation in vivo and significantly improved cardiac function and reduced fibrosis after myocardial infarction. Collectively, our findings present a cocktail FIJs that may be useful in cardiac regeneration and also provide a practical strategy for probing reprogramming assays for regeneration of other tissues.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Yan
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lundy
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Annie Ha
authors.initials: AH
authors.lastname: Lo
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Shu-Chian
authors.initials: SC
authors.lastname: Ruan
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Po-Ju
authors.initials: PJ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan phsieh@ibms.sinica.edu.tw.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Department of Surgery, Institute of Medical Genomics and Proteomics, Institute of Clinical Medicine, National Taiwan University & Hospital, Taipei, Taiwan.
authors.forename: Patrick Ch
authors.identifier: 0000-0002-8910-3596
authors.initials: PC
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000229:Dependovirus / Q000235:genetics; D000072278:Forkhead Box Protein M1 / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D008810:Mice, Inbred C57BL; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics; D009203:Myocardial Infarction / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D012038:Regeneration; D044968:Regenerative Medicine / Q000379:methods; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D000072278:Forkhead Box Protein M1; C491524:Foxm1 protein, mouse; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D034741:RNA, Small Interfering; D048057:Mitogen-Activated Protein Kinase 10
keywords: cardiomyocyte proliferation; gene therapy; heart regeneration; myocardial infarction; reprogramming