Generation of human endothelium in pig embryos deficient in ETV2

Nat Biotechnol. 2020 Mar;38(3):297-302. doi: 10.1038/s41587-019-0373-y. Epub 2020 Feb 24.

Abstract

The scarcity of donor organs may be addressed in the future by using pigs to grow humanized organs with lower potential for immunological rejection after transplantation in humans. Previous studies have demonstrated that interspecies complementation of rodent blastocysts lacking a developmental regulatory gene can generate xenogeneic pancreas and kidney1,2. However, such organs contain host endothelium, a source of immune rejection. We used gene editing and somatic cell nuclear transfer to engineer porcine embryos deficient in ETV2, a master regulator of hematoendothelial lineages3-7. ETV2-null pig embryos lacked hematoendothelial lineages and were embryonic lethal. Blastocyst complementation with wild-type porcine blastomeres generated viable chimeric embryos whose hematoendothelial cells were entirely donor-derived. ETV2-null blastocysts were injected with human induced pluripotent stem cells (hiPSCs) or hiPSCs overexpressing the antiapoptotic factor BCL2, transferred to synchronized gilts and analyzed between embryonic day 17 and embryonic day 18. In these embryos, all endothelial cells were of human origin.

Publication types

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

MeSH terms

  • Animals
  • Blastomeres / cytology*
  • Blastomeres / metabolism
  • Cells, Cultured
  • Embryo, Mammalian / metabolism*
  • Embryonic Development
  • Endothelium / cytology
  • Endothelium / metabolism*
  • Gene Editing
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / transplantation*
  • Nuclear Transfer Techniques
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Swine
  • Transcription Factors / deficiency*

Substances

  • BCL2 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors