P450 oxidoreductase regulates barrier maturation by mediating retinoic acid metabolism in a model of the human BBB

Dor Zlotnik, Tatiana Rabinski, Aviv Halfon, Shira Anzi, Inbar Plaschkes, Hadar Benyamini, Yuval Nevo, Orly Yahalom Gershoni, Benyamin Rosental, Eli Hershkovitz, Ayal Ben-Zvi, Gad D. Vatine

Research output: Contribution to journalArticlepeer-review

Abstract

The blood-brain barrier (BBB) selectively regulates the entry of molecules into the central nervous system (CNS). A crosstalk between brain microvascular endothelial cells (BMECs) and resident CNS cells promotes the acquisition of functional tight junctions (TJs). Retinoic acid (RA), a key signaling molecule during embryonic development, is used to enhance in vitro BBB models’ functional barrier properties. However, its physiological relevance and affected pathways are not fully understood. P450 oxidoreductase (POR) regulates the enzymatic activity of microsomal cytochromes. POR-deficient (PORD) patients display impaired steroid homeostasis and cognitive disabilities. Here, we used both patient-specific POR-deficient and CRISPR-Cas9-mediated POR-depleted induced pluripotent stem cell (iPSC)-derived BMECs (iBMECs) to study the role of POR in the acquisition of functional barrier properties. We demonstrate that POR regulates cellular RA homeostasis and that POR deficiency leads to the accumulation of RA within iBMECs, resulting in the impaired acquisition of TJs and, consequently, to dysfunctional development of barrier properties.

Original languageEnglish
Pages (from-to)2050-2063
Number of pages14
JournalStem Cell Reports
Volume17
Issue number9
DOIs
StateAccepted/In press - 2022

Keywords

  • BBB
  • blood-brain barrier
  • cytochrome
  • disease modeling
  • iPSCs
  • metabolism
  • P450 oxidoreductase
  • POR
  • retinoic acid
  • tight junctions

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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