In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes
Top Cited Papers
Open Access
- 18 April 2012
- journal article
- research article
- Published by Springer Nature in Nature
- Vol. 485 (7400), 593-598
- https://doi.org/10.1038/nature11044
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 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.Keywords
This publication has 40 references indexed in Scilit:
- Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overloadJCI Insight, 2010
- Cardiac fibroblasts: friend or foe?American Journal of Physiology-Heart and Circulatory Physiology, 2006
- Potential of stem-cell-based therapies for heart diseaseNature, 2006
- Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and ArrhythmogenesisCirculation Research, 2005
- Thymosin β: actin-sequestering protein moonlights to repair injured tissuesTrends in Molecular Medicine, 2005
- Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repairNature, 2004
- Temporally Regulated and Tissue-Specific Gene Manipulations in the Adult and Embryonic Heart Using a Tamoxifen-Inducible Cre ProteinCirculation Research, 2001
- Tie2-Cre Transgenic Mice: A New Model for Endothelial Cell-Lineage Analysis in VivoDevelopmental Biology, 2001
- Four Kinetically Distinct Depolarization-activated K+ Currents in Adult Mouse Ventricular MyocytesThe Journal of general physiology, 1999
- Generalized lacZ expression with the ROSA26 Cre reporter strainNature Genetics, 1999