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Article

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

by
Leonie Schumacher
1,
Rédouane Slimani
2,3,
Laimdota Zizmare
4,
Jakob Ehlers
1,
Felix Kleine Borgmann
2,3,
Julia C. Fitzgerald
5,
Petra Fallier-Becker
6,
Anja Beckmann
7,
Alexander Grißmer
7,
Carola Meier
7,
Ali El-Ayoubi
1,
Kavi Devraj
8,9,
Michel Mittelbronn
2,3,10,11,12,13,
Christoph Trautwein
4,* and
Ulrike Naumann
1,*
1
Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany
2
Department of Cancer Research (DOCR), Luxembourg Institute of Health (LIH), 1445 Strassen, Luxembourg
3
Luxembourg Centre of Neuropathology (LCNP), 3555 Dudelange, Luxembourg
4
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, 72076 Tübingen, Germany
5
Mitochondrial Biology of Parkinson’s Disease, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany
6
Institute for Pathology and Neuropathology, University of Tübingen, 72076 Tübingen, Germany
7
Department of Anatomy and Cell Biology, Saarland University, 66421 Homburg, Germany
8
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
9
Edinger Institute (Neurological Institute), Goethe University Hospital, 60528 Frankfurt am Main, Germany
10
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg
11
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg
12
Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg
13
National Center of Pathology (NCP), Laboratoire Nationale de Santé (LNS), 3555 Dudelange, Luxembourg
 
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*
Authors to whom correspondence should be addressed.
Biomedicines 2023, 11(1), 214; https://doi.org/10.3390/biomedicines11010214
Submission received: 16 December 2022 / Accepted: 11 January 2023 / Published: 14 January 2023
(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases 2.0)
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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.
Keywords: glioblastoma; blood–brain barrier; transforming growth factor beta; metabolomics glioblastoma; blood–brain barrier; transforming growth factor beta; metabolomics

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MDPI and ACS Style

Schumacher, L.; Slimani, R.; Zizmare, L.; Ehlers, J.; Kleine Borgmann, F.; Fitzgerald, J.C.; Fallier-Becker, P.; Beckmann, A.; Grißmer, A.; Meier, C.; et al. TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes. Biomedicines 2023, 11, 214. https://doi.org/10.3390/biomedicines11010214

AMA Style

Schumacher L, Slimani R, Zizmare L, Ehlers J, Kleine Borgmann F, Fitzgerald JC, Fallier-Becker P, Beckmann A, Grißmer A, Meier C, et al. TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes. Biomedicines. 2023; 11(1):214. https://doi.org/10.3390/biomedicines11010214

Chicago/Turabian Style

Schumacher, Leonie, Rédouane Slimani, Laimdota Zizmare, Jakob Ehlers, Felix Kleine Borgmann, Julia C. Fitzgerald, Petra Fallier-Becker, Anja Beckmann, Alexander Grißmer, Carola Meier, and et al. 2023. "TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes" Biomedicines 11, no. 1: 214. https://doi.org/10.3390/biomedicines11010214

APA Style

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. (2023). TGF-Beta Modulates the Integrity of the Blood Brain Barrier In Vitro, and Is Associated with Metabolic Alterations in Pericytes. Biomedicines, 11(1), 214. https://doi.org/10.3390/biomedicines11010214

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