title: Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult.
abstract: Understanding regulation of blood-brain barrier (BBB) is crucial to reduce/prevent its disruption during injury. As high brain complexity makes interpretation of in vivo data challenging, BBB studies are frequently performed using simplified in vitro models. However, many models fail to address the three-dimensional (3D) cellular interactions that occur in vivo, an important feature that may explain discrepancies in translation of in vitro data to the in vivo situation. We have designed and characterized an innovative 3D model that reproduces morphological and functional characteristics of the BBB in vivo and used it to investigate cellular interactions and contribution of astrocytes and pericytes to BBB development. Our model shows that both astrocytes and pericytes significantly suppress endothelial proliferation. In contrast, differential effects on tubulogenesis were observed with astrocytes reducing the number of tubes formed but increasing diameters and length, whereas pericytes had the opposite effect. Pericytes also induce proper localization of barrier proteins, lumen polarization, and functional activity of ATP-binding cassette (ABC) transporters similar to astrocytes, but the presence of both cells is required to maintain optimal barrier characteristics during hypoxic exposure. This model is simple, dynamic, and convenient to study many aspects of BBB function and represents an exciting new tool to address open questions of BBB regulation.
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
authors.forename: Abraham
authors.initials: A
authors.lastname: Al Ahmad
authors.forename: Carole Bürgi
authors.initials: CB
authors.lastname: Taboada
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Omolara O
authors.initials: OO
authors.lastname: Ogunshola
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D042501:Angiogenic Proteins / Q000096:biosynthesis; D000818:Animals; D001253:Astrocytes / Q000502:physiology* / Q000648:ultrastructure; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000502:physiology* / Q000648:ultrastructure; D002452:Cell Count; D018929:Cell Culture Techniques; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D002534:Hypoxia, Brain / Q000503:physiopathology*; D007150:Immunohistochemistry; D046529:Microscopy, Electron, Transmission; D008959:Models, Neurological; D018919:Neovascularization, Physiologic / Q000502:physiology; D020286:Pericytes / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D042501:Angiogenic Proteins; D003094:Collagen
references.citation: Methods Enzymol. 2008;443:83-101
references.pmid: 18772012
references.citation: Neuropharmacology. 2008 Sep;55(3):281-8
references.pmid: 18541276
references.citation: Mol Pharmacol. 2000 Dec;58(6):1357-67
references.pmid: 11093774
references.citation: Nature. 1987 Jan 15-21;325(6101):253-7
references.pmid: 3543687
references.citation: Biochem Biophys Res Commun. 2005 Feb 25;327(4):1114-23
references.pmid: 15652512
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 Sep;295(3):R864-73
references.pmid: 18614764
references.citation: J Cell Biol. 1969 Mar;40(3):648-77
references.pmid: 5765759
references.citation: Neuron. 2008 Jan 24;57(2):178-201
references.pmid: 18215617
references.citation: Curr Pharm Des. 2008;14(16):1555-65
references.pmid: 18673197
references.citation: Cytokine Growth Factor Rev. 2004 Aug;15(4):197-204
references.pmid: 15207811
references.citation: Methods Mol Med. 2003;89:375-82
references.pmid: 12958434
references.citation: Lancet Neurol. 2008 Jan;7(1):84-96
references.pmid: 18093565
references.citation: J Cereb Blood Flow Metab. 2003 Aug;23(8):879-94
references.pmid: 12902832
references.citation: Angiogenesis. 2007;10(1):35-45
references.pmid: 17225955
references.citation: Adv Exp Med Biol. 2003;543:89-115
references.pmid: 14713116
references.citation: Ophthalmic Res. 1994;26(1):23-31
references.pmid: 8134086
references.citation: Neurol Res. 2004 Dec;26(8):854-61
references.pmid: 15727269
references.citation: Curr HIV Res. 2006 Jul;4(3):259-66
references.pmid: 16842079
references.citation: Mol Pharmacol. 2004 Sep;66(3):413-9
references.pmid: 15322232
references.citation: Pharmacol Rev. 2005 Jun;57(2):173-85
references.pmid: 15914466
references.citation: Atherosclerosis. 1997 Apr;130(1-2):101-7
references.pmid: 9126653
references.citation: Pharmacol Res. 2009 Jun;59(6):404-13
references.pmid: 19429473
references.citation: Brain Res Dev Brain Res. 2000 Jan 3;119(1):139-53
references.pmid: 10648880
references.citation: Neurochem Int. 2009 Mar-Apr;54(3-4):253-63
references.pmid: 19111869
references.citation: Pharmacol Ther. 2008 May;118(2):206-30
references.pmid: 18439684
references.citation: J Cell Physiol. 1994 Apr;159(1):101-13
references.pmid: 7908023
references.citation: J Comp Neurol. 1997 Nov 3;387(4):537-46
references.pmid: 9373012
references.citation: Proc Natl Acad Sci U S A. 1979 Mar;76(3):1274-8
references.pmid: 286310
references.citation: J Cell Sci. 2007 May 15;120(Pt 10):1810-7
references.pmid: 17502485
references.citation: J Cell Physiol. 2009 Mar;218(3):612-22
references.pmid: 19016245
references.citation: Brain Res Dev Brain Res. 2001 Sep 23;130(1):123-32
references.pmid: 11557101
references.citation: Neuroscience. 2006;138(1):159-69
references.pmid: 16361063
references.citation: In Vitro Cell Dev Biol Anim. 1997 Oct;33(9):684-91
references.pmid: 9358284
references.citation: J Cereb Blood Flow Metab. 2007 Apr;27(4):697-709
references.pmid: 16850029
references.citation: J Neurochem. 1990 May;54(5):1798-801
references.pmid: 2182777
references.citation: J Physiol. 1990 Oct;429:47-62
references.pmid: 2277354
references.citation: J Neurovirol. 1999 Dec;5(6):556-69
references.pmid: 10602397
references.citation: Curr Neurovasc Res. 2008 Feb;5(1):71-81
references.pmid: 18289024