Three-dimensional heart extracellular matrix enhances chemically induced direct cardiac reprogramming

Abstract

Direct cardiac reprogramming has emerged as a promising therapeutic approach for cardiac regeneration. Full chemical reprogramming with small molecules to generate cardiomyocytes may be more amenable than genetic reprogramming for clinical applications as it avoids safety concerns associated with genetic manipula-tions. However, challenges remain regarding low conversion efficiency and incomplete cardiomyocyte matura-tion. Furthermore, the therapeutic potential of chemically induced cardiomyocytes (CiCMs) has not been investigated. Here, we report that a three-dimensional microenvironment reconstituted with decellularized heart extracellular matrix can enhance chemical reprogramming and cardiac maturation of fibroblasts to cardi-omyocytes. The resultant CiCMs exhibit elevated cardiac marker expression, sarcomeric organization, and im-proved electrophysiological features and drug responses. We investigated the therapeutic potential of CiCMs reprogrammed in three-dimensional heart extracellular matrix in a rat model of myocardial infarction. Our plat-form can facilitate the use of CiCMs for regenerative medicine, disease modeling, and drug screening.