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
Affiliations
Leonie Schumacher
Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany
Rédouane Slimani
Department of Cancer Research (DOCR), Luxembourg Institute of Health (LIH), 1445 Strassen, Luxembourg
Laimdota Zizmare
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, 72076 Tübingen, Germany
Jakob Ehlers
Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany
Felix Kleine Borgmann
Department of Cancer Research (DOCR), Luxembourg Institute of Health (LIH), 1445 Strassen, Luxembourg
Julia C. Fitzgerald
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
Petra Fallier-Becker
Institute for Pathology and Neuropathology, University of Tübingen, 72076 Tübingen, Germany
Anja Beckmann
Department of Anatomy and Cell Biology, Saarland University, 66421 Homburg, Germany
Alexander Grißmer
Department of Anatomy and Cell Biology, Saarland University, 66421 Homburg, Germany
Carola Meier
Department of Anatomy and Cell Biology, Saarland University, 66421 Homburg, Germany
Ali El-Ayoubi
Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany
Kavi Devraj
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
Michel Mittelbronn
Department of Cancer Research (DOCR), Luxembourg Institute of Health (LIH), 1445 Strassen, Luxembourg
Christoph Trautwein
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, 72076 Tübingen, Germany
Ulrike Naumann
Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany
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.
