(F1194) SUPPRESSING THE FIBROSIS-DETERMINING FACTOR MEOX1 ENABLES EFFICIENT IN VIVO REPROGRAMMING OF CARDIAC MYOFIBROBLASTS INTO CARDIOMYOCYTE-LIKE CELLS
Abstract: Direct reprogramming of cardiac fibroblasts (CFs) into induced cardiomyocyte-like cells (iCMs) is a promising regenerative medicine strategy for myocardial infarction (MI) patients. CFs are activated and transition to myofibroblasts (MFs) after MI, which are abundant in the injured area. However, MFs show extremely lower cardiac reprogramming efficiency. We identified Meox1, a TGF-β1 downstream transcription factor, which involved in cardiac fibrosis, as a barrier to cardiac reprogramming. In MFs induced with MGT (Mef2c, Gata4 and Tbx5) or MGT plus Myocd (MGTM), Meox1 knockdown results in significant increase in reprogramming efficiency. Single-cell analysis revealed meox1 as a central regulator in antagonistic transcriptional networks between fibrotic myofibroblasts and induced cardiomyocytes.Mutations disrupting the MEOX1 DNA binding domain or fusing it to a transcriptional repressor domain attenuate its inhibition of cardiac reprogramming. Furthermore, RNA-seq and CUT&Tag analysis revealed that Meox1 stabilizes a fibrosis-associated transcriptomic program and modulates the inflammatory response. Dual recombinase tracing showed that Meox1 knockdown enhances the efficiency of in vivo iCM reprogramming and restores cardiac function following myocardial infarction. Finally, we found that Meox1 knockdown improved reprogramming efficiency in human MFs. These findings provide a potential target for direct cardiac regeneration.
