Direct reprogramming induces vascular regeneration post muscle ischemic injury

Mol Ther. 2021 Oct 6;29(10):3042-3058. doi: 10.1016/j.ymthe.2021.07.014. Epub 2021 Jul 29.


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.

Keywords: cardiac repair; cardiac reprogramming; cardiovascular reprogramming; gene therapy; hindlimb ischemia; modified mRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cellular Reprogramming / genetics*
  • Disease Models, Animal
  • Female
  • Fibroblasts / metabolism
  • Genetic Therapy / methods*
  • Humans
  • Ischemia / therapy*
  • Male
  • Mice
  • Mice, Knockout, ApoE
  • Muscle, Skeletal / blood supply*
  • Myocardial Infarction / therapy*
  • Myocytes, Cardiac / metabolism
  • Neovascularization, Physiologic / genetics*
  • RNA, Messenger / genetics
  • Regeneration / genetics*
  • Transfection / methods*


  • RNA, Messenger