Direct reprogramming induces vascular regeneration post muscle ischemic injury

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 Kabir Sharkar, Ajit Magadum, Anthony Fargnoli, Seonghun Yoon, Elena Chepurko, Vadim Chepurko, Efrat Eliyahu, Dalila Pinto, Djamel LebecheJason C. Kovacic, Roger J. Hajjar, Shahin Rafii, Lior Zangi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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 a modified mRNA (modRNA) gene delivery platform to deliver a 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, and acid ceramidase (AC)—to induce CM-like cells. We showed that 7G-modRNA reprogrammed 57% of CM-like cells in vitro. Through a lineage-tracing model, we determined that delivering the 7G-modRNA cocktail at the time of myocardial infarction reprogrammed ∼25% of CM-like cells in the scar area and significantly improved cardiac function, scar size, long-term survival, and capillary density. Mechanistically, we determined that while 7G-modRNA cannot create de novo beating CMs in vitro or in vivo, it can significantly upregulate pro-angiogenic mesenchymal stromal cells markers and transcription factors. We also demonstrated that our 7G-modRNA cocktail leads to neovascularization in ischemic-limb injury, indicating CM-like cells importance in other organs besides the heart. modRNA is currently being used around the globe for vaccination against COVID-19, and this study proves this is a safe, highly efficient gene delivery approach with therapeutic potential to treat ischemic diseases.

Original languageAmerican English
Pages (from-to)3042-3058
Number of pages17
JournalMolecular Therapy
Volume29
Issue number10
DOIs
StatePublished - 6 Oct 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • cardiac repair
  • cardiac reprogramming
  • cardiovascular reprogramming
  • gene therapy
  • hindlimb ischemia
  • modified mRNA

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