FOXO3-Engineered Human ESC-Derived Vascular Cells Promote Vascular Protection and Regeneration

Cell Stem Cell. 2019 Mar 7;24(3):447-461.e8. doi: 10.1016/j.stem.2018.12.002. Epub 2019 Jan 17.


FOXO3 is an evolutionarily conserved transcription factor that has been linked to longevity. Here we wanted to find out whether human vascular cells could be functionally enhanced by engineering them to express an activated form of FOXO3. This was accomplished via genome editing at two nucleotides in human embryonic stem cells, followed by differentiation into a range of vascular cell types. FOXO3-activated vascular cells exhibited delayed aging and increased resistance to oxidative injury compared with wild-type cells. When tested in a therapeutic context, FOXO3-enhanced vascular cells promoted vascular regeneration in a mouse model of ischemic injury and were resistant to tumorigenic transformation both in vitro and in vivo. Mechanistically, constitutively active FOXO3 conferred cytoprotection by transcriptionally downregulating CSRP1. Taken together, our findings provide mechanistic insights into FOXO3-mediated vascular protection and indicate that FOXO3 activation may provide a means for generating more effective and safe biomaterials for cell replacement therapies.

Keywords: FOXO3; aging; gene editing; stem cell; vascular cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Differentiation
  • Disease Models, Animal
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism*
  • Forkhead Box Protein O3 / deficiency
  • Forkhead Box Protein O3 / genetics*
  • Forkhead Box Protein O3 / metabolism*
  • Genetic Engineering*
  • Humans
  • Ischemia / metabolism
  • Ischemia / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Regeneration*


  • FOXO3 protein, human
  • Forkhead Box Protein O3