TY - JOUR
T1 - TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes
AU - Schumacher, Leonie
AU - Slimani, Rédouane
AU - Zizmare, Laimdota
AU - Ehlers, Jakob
AU - Kleine Borgmann, Felix
AU - Fitzgerald, Julia C.
AU - Fallier-Becker, Petra
AU - Beckmann, Anja
AU - Grißmer, Alexander
AU - Meier, Carola
AU - El-Ayoubi, Ali
AU - Devraj, Kavi
AU - Mittelbronn, Michel
AU - Trautwein, Christoph
AU - Naumann, Ulrike
N1 - Funding Information:
C.T. reports a research grant by Bruker BioSpin GmbH, Ettlingen, Germany. All other authors declare no conflict of interest.
Funding Information:
We thank Hartwig Wolburg (Institute for Pathology and Neuropathology, University Hospital Tübingen) for his help for the quantification of TJs, and Ria Knittel for technical help with the freeze fracture. We also thank Martin Schenk (Experimental Surgery, University Hospital Tübingen) for the provision of pig brains. We thank Werner Siemens Foundation, Bernd Pichler for financial support, and Miriam Owczorz for excellent technical support. MM would like to thank the Luxembourg National Research Fond (FNR) for the support (FNR PEARL P16/BM/11192868 grant).
Funding Information:
The study was funded by a scholarship to L.S. from the IZKF Promotionskolleg of the Medical Faculty, University of Tübingen. Costs for publication were financed in part by the Open Access Publication Fund of the University Tübingen.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/1/14
Y1 - 2023/1/14
N2 - 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.
AB - 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.
KW - blood–brain barrier
KW - glioblastoma
KW - metabolomics
KW - transforming growth factor beta
UR - http://www.scopus.com/inward/record.url?scp=85146817800&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/36672722
U2 - 10.3390/biomedicines11010214
DO - 10.3390/biomedicines11010214
M3 - Article
C2 - 36672722
SN - 2227-9059
VL - 11
JO - Biomedicines
JF - Biomedicines
IS - 1
M1 - 214
ER -