Engineering of human brain organoids with a functional vascular-like system

Nat Methods. 2019 Nov;16(11):1169-1175. doi: 10.1038/s41592-019-0586-5. Epub 2019 Oct 7.


Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.

Publication types

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

MeSH terms

  • Animals
  • Blood-Brain Barrier
  • Brain / blood supply*
  • Cells, Cultured
  • Human Embryonic Stem Cells / cytology*
  • Humans
  • Mice
  • Organoids / blood supply*
  • Single-Cell Analysis
  • Tissue Engineering / methods*
  • Transcription Factors / physiology


  • ETV2 protein, human
  • Transcription Factors