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Yoonhee Jin†, Hyeok Kim†, Sungjin Min, Yi Sun Choi, Seung Ju Seo, Eunseon Jeong, Su Kyeom Kim, Hyang-Ae Lee, Sung-Hyun Jo, Jae-Hyun Park, Bong-Woo Park, Woo-Sup Sim, Jin-Ju Kim, Kiwon Ban, Yun-Gon Kim, Hun-Jun Park*, and Seung-Woo Cho* († equally contributed)
Three-Dimensional Heart Extracellular Matrix Enhances Chemically Induced Direct Cardiac Reprogramming
Sci. Adv., 8 (50), 1-20
Date: Dec 14, 2022

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 manipulations. However, challenges remain regarding low conversion efficiency and incomplete cardiomyocyte maturation. 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 cardiomyocytes. The resultant CiCMs exhibit elevated cardiac marker expression, sarcomeric organization, and improved 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 platform can facilitate the use of CiCMs for regenerative medicine, disease modeling, and drug screening.

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