Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts

Nat Biomed Eng. 2021 Aug;5(8):880-896. doi: 10.1038/s41551-021-00783-0. Epub 2021 Aug 23.


Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.

Publication types

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

MeSH terms

  • Animals
  • Ascorbic Acid / pharmacology
  • Bone Morphogenetic Protein 4 / pharmacology
  • Cellular Reprogramming / drug effects
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Endothelial Cells / transplantation*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gap Junctions / physiology
  • Heart / physiology*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • Myocardial Infarction / therapy*
  • Myocardium / cytology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / transplantation*
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Neovascularization, Physiologic
  • Regeneration*
  • Transcriptome


  • Bone Morphogenetic Protein 4
  • MicroRNAs
  • Mirn208 microRNA, mouse
  • Myh6 protein, mouse
  • Myosin Heavy Chains
  • Ascorbic Acid