Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes

• Published in: Scientific reports Vol. 10; no. 1; p. 7129
• Main Authors: Testa, Gianluca, Russo, Michele, Di Benedetto, Giorgia, Barbato, Matteo, Parisi, Silvia, Pirozzi, Flora, Tocchetti, Carlo Gabriele, Abete, Pasquale, Bonaduce, Domenico, Russo, Tommaso, Passaro, Fabiana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-04-2020; Nature Publishing Group
• Subjects: 13/95; 14; 38; 38/77; 38/91; 631/136/2128; 631/136/2435; 631/61/490; 82/29; 96/106; 96/95; Animals; Biomarkers - metabolism; Calcium-binding protein; Cardiac Myosins - metabolism; Cardiomyocytes; Cellular Reprogramming - drug effects; Chemokines; Down-Regulation; Embryo fibroblasts; Fibroblasts; Fibroblasts - drug effects; Gene expression; Gene regulation; Gene silencing; Heterocyclic Compounds, 2-Ring - pharmacology; Humanities and Social Sciences; Inflammation; MAP kinase; Mice; multidisciplinary; Myocardium; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myosin; Myosin Light Chains - metabolism; Polycomb Repressive Complex 1 - antagonists & inhibitors; Polycomb Repressive Complex 1 - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Signal Transduction; Stat3 protein; Thiazoles - pharmacology; Troponin; Troponin T; Troponin T - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-63992-8

The development of therapeutic approaches based on direct cardiac reprogramming of fibroblasts into induced-cardiomyocytes (iCM) has emerged as an attractive strategy to repair the injured myocardium. The identification of the mechanisms driving lineage conversion represents a crucial step toward the development of new and more efficient regenerative strategies. To this aim, here we show that pre-treatment with the Bmi1 inhibitor PTC-209 is sufficient to increase the efficiency of Chemical-induced Direct Cardiac Reprogramming both in mouse embryonic fibroblasts and adult cardiac fibroblasts. PTC-209 induces an overall increase of spontaneously beating iCM at end-stage of reprogramming, expressing high levels of late cardiac markers Troponin T and myosin muscle light chain-2v. The inhibition of Bmi1 expression occurring upon PTC-209 pre-treatment was maintained throughout the reprogramming protocol, contributing to a significant gene expression de-regulation. RNA profiling revealed that, upon Bmi1 inhibition a significant down-regulation of genes associated with immune and inflammatory signalling pathways occurred, with repression of different genes involved in interleukin, cytokine and chemokine pathways. Accordingly, we observed the down-regulation of both JAK/STAT3 and MAPK/ERK1-2 pathway activation, highlighting the crucial role of these pathways as a barrier for cardiac reprogramming. These findings have significant implications for the development of new cardiac regenerative therapies.