title: In vivo reprogramming of murine cardiac  fibroblasts into induced cardiomyocytes.
abstract: The reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types holds great promise for regenerative medicine. We reported previously that cardiac fibroblasts,which represent 50%of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Here we use genetic lineage tracing to show that resident non-myocytes in the murine heart can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of GMT after coronary ligation. Induced cardiomyocytes became binucleate, assembled sarcomeres and had cardiomyocyte-like gene expression. Analysis of single cells revealed ventricular cardiomyocyte-like action potentials, beating upon electrical stimulation, and evidence of electrical coupling. In vivo delivery of GMT decreased infarct size and modestly attenuated cardiac dysfunction up to 3 months after coronary ligation. Delivery of the pro-angiogenic and fibroblast-activating peptide, thymosin b4, along with GMT, resulted in further improvements in scar area and cardiac function. These findings demonstrate that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes.
authors.affiliation: 1Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: C Ian
authors.initials: CI
authors.lastname: Spencer
authors.forename: Amy
authors.initials: A
authors.lastname: Foley
authors.forename: Vasanth
authors.initials: V
authors.lastname: Vedantham
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Ji-dong
authors.initials: JD
authors.lastname: Fu
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming; D002921:Cicatrix / Q000473:pathology / Q000628:therapy; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D044968:Regenerative Medicine / Q000379:methods*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D013947:Thymosin / Q000494:pharmacology / Q000627:therapeutic use; D000099201:Thymosin beta(4)
chemical_list: D015415:Biomarkers; D050991:GATA4 Transcription Factor; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D020825:T-Box Domain Proteins; D013947:Thymosin; D000099201:Thymosin beta(4); C484171:Gata4 protein, mouse; C578041:Mef2c protein, mouse; C103172:T-box transcription factor 5