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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers / analysis
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Cell Lineage
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Cell Transdifferentiation*
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Cellular Reprogramming*
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Cicatrix / pathology
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Cicatrix / therapy
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Female
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Fibroblasts / cytology*
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / pathology
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GATA4 Transcription Factor / genetics
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GATA4 Transcription Factor / metabolism
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Gene Expression Regulation
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Genetic Vectors / genetics
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Heart / physiology
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Heart / physiopathology
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MEF2 Transcription Factors
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Male
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Mice
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Myocardial Infarction / drug therapy
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardial Infarction / therapy
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Myocardium / cytology
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Myocardium / pathology
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Myocytes, Cardiac / cytology*
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Myocytes, Cardiac / physiology*
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Myogenic Regulatory Factors / genetics
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Myogenic Regulatory Factors / metabolism
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Regenerative Medicine / methods*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism
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Thymosin / pharmacology
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Thymosin / therapeutic use
Substances
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Biomarkers
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GATA4 Transcription Factor
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Gata4 protein, mouse
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MEF2 Transcription Factors
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Mef2c protein, mouse
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Myogenic Regulatory Factors
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T-Box Domain Proteins
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T-box transcription factor 5
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thymosin beta(4)
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Thymosin