Direct reprogramming induces vascular regeneration post muscle ischemic injury

• DOI: 10.1016/j.ymthe.2021.07.014
• Publication Date: 2021-07-29T02:20:18Z
• Authors: Keerat Kaur; Yoav Hadas; Ann Anu Kurian; Magdalena M. Żak; Jimeen Yoo; Asharee Mahmood; Hanna Girard; Rinat Komargodski; Toshiro Io; Maria Paola Santini; Nishat Sultana; Mohammad Tofael K...; Ajit Magadum; Anthony Fargnoli; Seonghun Yoon; Elena Chepurko; Vadim Chepurko; Efrat Eliyahu; Dalila Pinto; Djamel Lebeche; Jason C. Kovacic; Roger J. Hajjar; Shahin Rafii; Lior Zangi
• Keywords: Reprogramming

Reprogramming non-cardiomyocytes (non-CMs) into cardiomyocyte (CM)-like cells is a promising strategy for cardiac regeneration in conditions such as ischemic heart disease. Here, we used modified mRNA (modRNA) gene delivery platform to deliver cocktail, termed 7G-modRNA, of four cardiac-reprogramming genes-Gata4 (G), Mef2c (M), Tbx5 (T), and Hand2 (H)-together with three reprogramming-helper genes-dominant-negative (DN)-TGFβ, DN-Wnt8a, acid ceramidase (AC)-to induce CM-like cells. We showed that 7G-modRNA reprogrammed 57% vitro. Through lineage-tracing model, determined delivering the cocktail at time myocardial infarction ∼25% scar area significantly improved function, size, long-term survival, capillary density. Mechanistically, while cannot create de novo beating CMs vitro or vivo, it can upregulate pro-angiogenic mesenchymal stromal markers transcription factors. also demonstrated our leads neovascularization ischemic-limb injury, indicating importance other organs besides heart. modRNA currently being around globe vaccination against COVID-19, this study proves safe, highly efficient approach therapeutic potential treat diseases.