Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate Journal Article


Authors: Lu, T. M.; Houghton, S.; Magdeldin, T.; Barcia Durán, J. G.; Minotti, A. P.; Snead, A.; Sproul, A.; Nguyen, D. H. T.; Xiang, J.; Fine, H. A.; Rosenwaks, Z.; Studer, L.; Rafii, S.; Agalliu, D.; Redmond, D.; Lis, R.
Article Title: Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate
Abstract: Cells derived from pluripotent sources in vitro must resemble those found in vivo as closely as possible at both transcriptional and functional levels in order to be a useful tool for studying diseases and developing therapeutics. Recently, differentiation of human pluripotent stem cells (hPSCs) into brain microvascular endothelial cells (ECs) with blood–brain barrier (BBB)-like properties has been reported. These cells have since been used as a robust in vitro BBB model for drug delivery and mechanistic understanding of neurological diseases. However, the precise cellular identity of these induced brain microvascular endothelial cells (iBMECs) has not been well described. Employing a comprehensive transcriptomic metaanalysis of previously published hPSC-derived cells validated by physiological assays, we demonstrate that iBMECs lack functional attributes of ECs since they are deficient in vascular lineage genes while expressing clusters of genes related to the neuroectodermal epithelial lineage (Epi-iBMEC). Overexpression of key endothelial ETS transcription factors (ETV2, ERG, and FLI1) reprograms Epi-iBMECs into authentic endothelial cells that are congruent with bona fide endothelium at both transcriptomic as well as some functional levels. This approach could eventually be used to develop a robust human BBB model in vitro that resembles the human brain EC in vivo for functional studies and drug discovery. © 2021 National Academy of Sciences. All rights reserved.
Keywords: endothelial cells; cellular identity; blood–brain barrier; single-cell rna sequencing; induced pluripotent
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 118
Issue: 8
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2021-02-23
Start Page: e2016950118
Language: English
DOI: 10.1073/pnas.2016950118
PUBMED: 33542154
PROVIDER: scopus
PMCID: PMC7923590
DOI/URL:
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
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