Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

TGF-beta Modulates the Integrity of the Blood Brain Barrier in Vitro, and is Associated with Metabolic Alterations in Pericytes

Leonie Schumacher
,
Redouane Slimani
,
Laimdota Zizmare
ORCID logo ,
Jakob Ehlers
,
Felix Kleine Borgmann
,
Julia C. Fitzgerald
ORCID logo ,
Petra Fallier-Becker
,
Anja Beckmann
,
Alexander Grißmer
ORCID logo ,
Carola Meier
,
Ali El-Ayoubi
,
Kavi Devraj
,
Michel Mittelbronn
,
Christoph Trautwein
ORCID logo ,
Ulrike Naumann
* ORCID logo
Version 1 : Received: 16 December 2022 / Approved: 20 December 2022 / Online: 20 December 2022 (01:19:48 CET)

A peer-reviewed article of this Preprint also exists.

Schumacher, L.; Slimani, R.; Zizmare, L.; Ehlers, J.; Kleine Borgmann, F.; Fitzgerald, J.C.; Fallier-Becker, P.; Beckmann, A.; Grißmer, A.; Meier, C.; El-Ayoubi, A.; Devraj, K.; Mittelbronn, M.; Trautwein, C.; Naumann, U. TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes. Biomedicines 2023, 11, 214. Schumacher, L.; Slimani, R.; Zizmare, L.; Ehlers, J.; Kleine Borgmann, F.; Fitzgerald, J.C.; Fallier-Becker, P.; Beckmann, A.; Grißmer, A.; Meier, C.; El-Ayoubi, A.; Devraj, K.; Mittelbronn, M.; Trautwein, C.; Naumann, U. TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes. Biomedicines 2023, 11, 214.

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 maintain the BBB integrity, can be functionally modified by GBM cells by inducing 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 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, finally leading to the disruption of a so far intact and tight BBB. TGF-β dramatically changed the metabolic behavior of pericytes, such as shutting down the TCA cycle, driving energy generation from oxidative phosphorylation towards glycolysis, and by shifting the cells towards the activation of pathways that are necessary to produce molecules used for proliferation and cell division. Furthermore, combined metabolomics and RNASeq analyses indicated that the observed functional changes of TGF-β-treated pericytes are closely connected with their behavior.

Keywords

Glioblastoma; blood brain barrier; transforming growth factor beta; NMR metabolomics

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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