TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes

Leonie Schumacher, Rédouane Slimani, Laimdota Zizmare, Jakob Ehlers, Felix Kleine Borgmann, Julia C. Fitzgerald, Petra Fallier-Becker, Anja Beckmann, Alexander Grißmer, Carola Meier, Ali El-Ayoubi, Kavi Devraj, Michel Mittelbronn, Christoph Trautwein*, Ulrike Naumann*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

The blood–brain barrier (BBB) is a selectively permeable boundary that separates the circulating blood from the extracellular fluid of the brain and is an essential component for brain homeostasis. In glioblastoma (GBM), the BBB of peritumoral vessels is often disrupted. Pericytes, being important to maintaining BBB integrity, can be functionally modified by GBM cells which induce proliferation and cell motility via the TGF-β-mediated induction of central epithelial to mesenchymal transition (EMT) factors. We demonstrate that pericytes strengthen the integrity of the BBB in primary endothelial cell/pericyte co-cultures as an in vitro BBB model, using TEER measurement of the barrier integrity. In contrast, this effect was abrogated by TGF-β or conditioned medium from TGF-β secreting GBM cells, leading to the disruption of a so far intact and tight BBB. TGF-β notably changed the metabolic behavior of pericytes, by shutting down the TCA cycle, driving energy generation from oxidative phosphorylation towards glycolysis, and by modulating pathways that are necessary for the biosynthesis of molecules used for proliferation and cell division. Combined metabolomic and transcriptomic analyses further underscored that the observed functional and metabolic changes of TGF-β-treated pericytes are closely connected with their role as important supporting cells during angiogenic processes.

Original languageEnglish
Article number214
JournalBiomedicines
Volume11
Issue number1
DOIs
Publication statusPublished - 14 Jan 2023

Keywords

  • blood–brain barrier
  • glioblastoma
  • metabolomics
  • transforming growth factor beta

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