The blood-brain barrier (BBB) is crucial to the health of the brain and is often compromised in neurological disease. Moreover, because of its barrier properties, this endothelial interface restricts uptake of neurotherapeutics. Thus, a renewable source of human BBB endothelium could spur brain research and pharmaceutical development. Here we show that endothelial cells derived from human pluripotent stem cells (hPSCs) acquire BBB properties when co-differentiated with neural cells that provide relevant cues, including those involved in Wnt/β-catenin signaling. The resulting endothelial cells have many BBB attributes, including well-organized tight junctions, appropriate expression of nutrient transporters and polarized efflux transporter activity. Notably, they respond to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance (1,450 α 140 ω cm2), and they possess molecular permeability that correlates well with in vivo rodent blood-brain transfer coefficients.
Bibliographical noteFunding Information:
This work was funded in part by US National Institutes of Health (NIH) grants NS056249 (E.V.S.), AA020476 (E.V.S.) and EB007534 (S.P.P.) and US National Science Foundation (NSF) grant EFRI-0735903 (S.P.P.). E.S.L. is a recipient of a NIH Chemistry Biology Interface traineeship (T32 GM008505) and S.M.A. is the recipient of a NSF Graduate Research fellowship. We thank the WiCell Research Institute for providing research support and W.M. Pardridge (University of California–Los Angeles) for the gift of GLUT-1 antiserum.