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 β4, 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.
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We are grateful for technical assistance from the Gladstone Histology Core (C. Miller), Gladstone Genomics Core (L. Ta, Y. Hao, B. Chadwick), UCSF MRI Core (M. Wendland, J. Hawkins) and Laboratory for Cell Analysis at UCSF (S. Elmes). We thank all the members of the Srivastava laboratory for helpful discussions; G. Howard and B. Taylor for editorial help; and B. Bruneau and B. Conklin for helpful discussions and critical reviews of the manuscript. We also thank J. Nerbonne, N. Foeger, and members of the Nerbonne laboratory for assistance with the adult myocyte isolation protocol. L.Q. is a postdoctoral scholar of the California Institute for Regenerative Medicine (CIRM). V.V. is supported by grants from the GlaxoSmithKline Research and Education Foundation and the NIH/NHLBI (K08HL101989). J.-d.F. is supported by a postdoctoral fellowship from American Heart Association. S.J.C. was supported by R01 HL060714 from NHLBI/NIH. D.S. was supported by grants from NHLBI/NIH, CIRM, the Younger Family Foundation, Roddenberry Foundation and the L.K. Whittier Foundation. This work was supported by NIH/NCRR grant (C06 RR018928) to the Gladstone Institutes.
This file contains four videomicroscopy segments, edited together, showing a pair of Fluo-4-loaded myocytes – see Supplementary Information file for full legend.
This file contains a high-speed camera recording shows contraction of an induced cardiomyocyte (iCM) and an endogenous cardiomyocyte (CM) upon electrical stimulation – see Supplementary Information file for full legend.