High and low permeability of human pluripotent stem cell–derived blood–brain barrier models depend on epithelial or endothelial features - Archive ouverte HAL
Journal Articles (Data Paper) FASEB Journal Year : 2023

High and low permeability of human pluripotent stem cell–derived blood–brain barrier models depend on epithelial or endothelial features

Stéphane D Girard
  • Function : Author
Ingrid Julien-Gau
  • Function : Author
Yves Molino
  • Function : Author
Benjamin F Combes
  • Function : Author
Louise Greetham
  • Function : Author
Emmanuel Nivet

Abstract

Abstract The search for reliable human blood–brain barrier (BBB) models represents a challenge for the development/testing of strategies aiming to enhance brain delivery of drugs. Human‐induced pluripotent stem cells (hiPSCs) have raised hopes in the development of predictive BBB models. Differentiating strategies are thus required to generate endothelial cells (ECs), a major component of the BBB. Several hiPSC‐based protocols have reported the generation of in vitro models with significant differences in barrier properties. We studied in depth the properties of iPSCs byproducts from two protocols that have been established to yield these in vitro barrier models. Our analysis/study reveals that iPSCs derivatives endowed with EC features yield high permeability models while the cells that exhibit outstanding barrier properties show principally epithelial cell‐like (EpC) features. We found that models containing EpC‐like cells express tight junction proteins, transporters/efflux pumps and display a high functional tightness with very low permeability, which are features commonly shared between BBB and epithelial barriers. Our study demonstrates that hiPSC‐based BBB models need extensive characterization beforehand and that a reliable human BBB model containing EC‐like cells and displaying low permeability is still needed.

Keywords

BSA, bovine serum albumin CNS, central nervous system CspA, cyclosporin A EC, endothelial cell ECEM, endothelial cell expansion medium ECIM, endothelial cell induction medium ECM, extracelullar matrix EpC, epithelial cell FPKM, fragment per kilobase million GSK3β, glycogen synthase kinase 3 beta HBMVECs, human brain microvascular endothelial cells hiPSCs, human-induced pluripotent stem cells HUVECs, human umbilical vein endothelial cells LY, lucifer yellow MACS, magnetic activated cell sorting NVU, neurovascular unit Pe, permeability Pr-1, protocol 1 PSCs, pluripotent stem cells RA, retinoic acid RPKM, read per kilobase million TEER, trans-endothelial electrical resistance TGFβ, transforming growth factor beta TNF-α, tumor necrosis factor-alpha Ac-LDL, acetylated low-density lipoprotein BBB, blood-brain barrier bFGF, basic fibroblast growth factor BMP4, bone morphogenic protein 4 BMVEC, brain microvascular endothelial cells BSA, bovine serum albumin CNS, central nervous system CspA, cyclosporin A EC, endothelial cell ECEM, endothelial cell expansion medium ECIM, endothelial cell induction medium ECM, extracelullar matrix EpC, epithelial cell FPKM, fragment per kilobase million GSK3β, glycogen synthase kinase 3 beta HBMVECs, human brain microvascular endothelial cells hiPSCs, human-induced pluripotent stem cells HUVECs, human umbilical vein endothelial cells LY, lucifer yellow MACS, magnetic activated cell sorting NVU, neurovascular unit Pe, permeability Pr-1, protocol 1 PSCs, pluripotent stem cells RA, retinoic acid RPKM, read per kilobase million TEER, trans-endothelial electrical resistance TGFβ, transforming growth factor beta TNF-α, tumor necrosis factor-alpha UM, unconditioned medium VEGF, vascular endothelial growth factor UM, unconditioned medium Ac-LDL, acetylated low-density lipoprotein VEGF, vascular endothelial growth factor BBB, blood-brain barrier bFGF, basic fibroblast growth factor BMP4, bone morphogenic protein 4 BMVEC, brain microvascular endothelial cells BSA, bovine serum albumin BSA, bovine serum albumin BSA, bovine serum albumin
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Dates and versions

hal-04300615 , version 1 (22-11-2023)

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Stéphane D Girard, Ingrid Julien-Gau, Yves Molino, Benjamin F Combes, Louise Greetham, et al.. High and low permeability of human pluripotent stem cell–derived blood–brain barrier models depend on epithelial or endothelial features. FASEB Journal, 2023, 37 (2), ⟨10.1096/fj.202201422R⟩. ⟨hal-04300615⟩
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