Abstract 15383: Direct Conversion of Cardiac Fibroblasts into Cardiomyocyte-Like Cells in vivo
Background Loss of terminally differentiated cardiomyocytes due to myocardial damage is irreversible and current therapeutic regimes are limited. Regenerative medicine is an attractive option to repair injured hearts. We recently found that a combination of transcription factors reprograms cardiac fibroblasts directly into differentiated cardiomyocyte-like cells in vitro. This study was designed to investigate whether direct injection of cardiac reprogramming factors into the infarct hearts can convert endogenous cardiac fibroblasts into cardiomyocytes in vivo.
Methods and Results Coronary artery ligation was employed to induce myocardial infarction in mouse and retroviral vectors were used for gene transfer. The number of cardiac fibroblasts which express vimentin was significantly increased after myocardial infarction. To determine if reprogramming factors could induce cardiac transdifferentiation in vivo, we injected either a pool of Gata4, Mef2c, Tbx5 (GMT) and DsRed or a control DsRed retrovirus into the a-myosin heavy chain (MHC) GFP mouse hearts, in which only differentiated cardiomyocytes express GFP. Cardiac fibroblasts infected with DsRed did not express a-MHC GFP, confirming cardiomyocyte conversion did not happen in the negative control. In contrast, after GMT and DsRed local delivery, double immunostaining demonstrated that the cells in the infarct area expressed both DsRed and a-MHC GFP. Moreover, the DsRed positive cells expressed sarcomeric α-actinin, a marker of cardiomyocytes, and had clear sarcomeric structures. We also found that cardiac conversion was more prominent in the border zone (5% of fiborblasts) compared with in the scar area.
Conclusions These results indicate that endogenous cardiac fibroblasts can be a cell source for new cardiomyocytes and that direct cardiac reprogramming can be induced in vivo by local delivery of GMT into the infarct heart. Modifications of this strategy might provide new contractile tissues to repair infarct hearts.
- © 2011 by American Heart Association, Inc.