Wnt signaling mediates acquisition of blood-brain barrier properties in naïve endothelium derived from human pluripotent stem cells
- University of Wisconsin-Madison, United States
- University of Bern, Switzerland
Abstract
Endothelial cells (ECs) in the central nervous system (CNS) acquire their specialized blood-brain barrier (BBB) properties in response to extrinsic signals, with Wnt/β-catenin signaling coordinating multiple aspects of this process. Our knowledge of CNS EC development has been advanced largely by animal models, and human pluripotent stem cells (hPSCs) offer the opportunity to examine BBB development in an in vitro human system. Here we show that activation of Wnt signaling in hPSC-derived naïve endothelial progenitors, but not in matured ECs, leads to robust acquisition of canonical BBB phenotypes including expression of GLUT-1, increased claudin-5, decreased PLVAP and decreased permeability. RNA-seq revealed a transcriptome profile resembling ECs with CNS-like characteristics, including Wnt-upregulated expression of LEF1, APCDD1, and ZIC3. Together, our work defines effects of Wnt activation in naïve ECs and establishes an improved hPSC-based model for interrogation of CNS barriergenesis.
Data availability
RNA-seq data have been deposited in GEO under accession number GSE173206.
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Transcriptional and Epigenomic Landscapes of CNS and non-CNS Vascular Endothelial CellsGSM3040844 GSM3040845 GSM3040852 GSM3040853 GSM3040858 GSM3040859 GSM3040864 GSM3040865.
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Gene expression profiles of liver and lung endothelial cells during normal and upregulation of Wnt/beta-catenin signalingGSM2498580 GSM2498581 GSM2498582 GSM2498583 GSM2498584 GSM2498585 GSM2498586 GSM2498587.
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The role of beta-catenin signaling in regulating barrier vs. non-barrier gene expression programs in circumventricular organ and ocular vasculaturesGSM3455653 GSM3455654 GSM3455657 GSM3455658 GSM3455661 GSM3455662 GSM3455665 GSM3455666.
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A genome-wide view of the de-differentiation of central nervous system endothelial cells in cultureGSM4160534 GSM4160535 GSM4160536 GSM4160537 GSM4160538 GSM4160539 GSM4160540 GSM4160541 GSM4160542 GSM4160543.
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Construction of A Human Cell Landscape by Single-cell mRNA-seqGSM3980129 GSM4008656 GSM4008657 GSM4008658.
Article and author information
Author details
Benjamin D Gastfriend
Funding
National Institutes of Health (R01 NS103844)
- Sean P Palecek
- Eric V Shusta
National Institutes of Health (R01 NS107461)
- Sean P Palecek
- Eric V Shusta
National Institutes of Health (T32 GM008349)
- Benjamin D Gastfriend
National Science Foundation (1747503)
- Benjamin D Gastfriend
Swiss National Science Foundation (310030_189080)
- Britta Engelhardt
Bern Center for Precision Medicine
- Britta Engelhardt
Japan Society for the Promotion of Science (Overseas Research Fellowship)
- Hideaki Nishihara
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Stefan Liebner, University Hospital, Goethe University Frankfurt, Germany
Version history
- Preprint posted: May 14, 2021 (view preprint)
- Received: June 4, 2021
- Accepted: November 9, 2021
- Accepted Manuscript published: November 10, 2021 (version 1)
- Accepted Manuscript updated: November 12, 2021 (version 2)
- Version of Record published: December 10, 2021 (version 3)
Copyright
© 2021, Gastfriend et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Wnt signaling mediates acquisition of blood-brain barrier properties in naïve endothelium derived from human pluripotent stem cells
eLife 10:e70992.
https://doi.org/10.7554/eLife.70992
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