Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Fluids and Barriers of the CNS
Published in: Fluids and Barriers of the CNS 1/2018

Open Access 01-12-2018 | Review

Benchmarking in vitro tissue-engineered blood–brain barrier models

Authors: Jackson G. DeStefano, John J. Jamieson, Raleigh M. Linville, Peter C. Searson

Published in: Fluids and Barriers of the CNS | Issue 1/2018

Login to get access

Abstract

The blood–brain barrier (BBB) plays a key role in regulating transport into and out of the brain. With increasing interest in the role of the BBB in health and disease, there have been significant advances in the development of in vitro models. The value of these models to the research community is critically dependent on recapitulating characteristics of the BBB in humans or animal models. However, benchmarking in vitro models is surprisingly difficult since much of our knowledge of the structure and function of the BBB comes from in vitro studies. Here we describe a set of parameters that we consider a starting point for benchmarking and validation. These parameters are associated with structure (ultrastructure, wall shear stress, geometry), microenvironment (basement membrane and extracellular matrix), barrier function (transendothelial electrical resistance, permeability, efflux transport), cell function (expression of BBB markers, turnover), and co-culture with other cell types (astrocytes and pericytes). In suggesting benchmarks, we rely primarily on imaging or direct measurements in humans and animal models.
Literature
1.
2.
3.
Wilson HK, et al. Exploring the effects of cell seeding density on the differentiation of human pluripotent stem cells to brain microvascular endothelial cells. Fluids Barriers CNS. 2015;12:13.CrossRefPubMedPubMedCentral
4.
Katt ME, et al. Human brain microvascular endothelial cells derived from the BC1 iPS cell line exhibit a blood–brain barrier phenotype. PLoS ONE. 2016;11(4):e0152105.CrossRefPubMedPubMedCentral
5.
Mantle JL, Min L, Lee KH. Minimum transendothelial electrical resistance thresholds for the study of small and large molecule drug transport in a human in vitro blood–brain barrier model. Mol Pharm. 2016;13(12):4191–8.CrossRefPubMed
6.
Patel R, Alahmad AJ. Growth-factor reduced Matrigel source influences stem cell derived brain microvascular endothelial cell barrier properties. Fluids Barriers CNS. 2016;13:6.CrossRefPubMedPubMedCentral
7.
Page S, Munsell A, Al-Ahmad AJ. Cerebral hypoxia/ischemia selectively disrupts tight junctions complexes in stem cell-derived human brain microvascular endothelial cells. Fluids Barriers CNS. 2016;13:16.CrossRefPubMedPubMedCentral
8.
Gallagher E, et al. In vitro characterization of pralidoxime transport and acetylcholinesterase reactivation across MDCK cells and stem cell-derived human brain microvascular endothelial cells (BC1-hBMECs). Fluids Barriers CNS. 2016;13(1):10.CrossRefPubMedPubMedCentral
9.
Appelt-Menzel A, et al. Establishment of a human blood–brain barrier co-culture model mimicking the neurovascular unit using induced pluri- and multipotent stem cells. Stem Cell Rep. 2017;8(4):894–906.CrossRef
10.
Hollmann EK, et al. Accelerated differentiation of human induced pluripotent stem cells to blood–brain barrier endothelial cells. Fluids Barriers CNS. 2017;14:9.CrossRefPubMedPubMedCentral
11.
Al-Ahmad AJ. Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells. Am J Physiol Cell Physiol. 2017;313(4):C421–9.CrossRefPubMedPubMedCentral
12.
Kim BJ, et al. Modeling group B Streptococcus and blood–brain barrier interaction by using induced pluripotent stem cell-derived brain endothelial cells. Msphere. 2017;2(6):e00398-17.CrossRefPubMedPubMedCentral
13.
Kokubu Y, Yamaguchi T, Kawabata K. In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells. Biochem Biophys Res Commun. 2017;486:577–83.CrossRefPubMed
14.
Lim RG, et al. Huntington’s disease iPSC-derived brain microvascular endothelial cells reveal WNT-mediated angiogenic and blood–brain barrier deficits. Cell Rep. 2017;19(7):1365–77.CrossRefPubMedPubMedCentral
15.
Canfield SG, et al. An isogenic blood–brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. J Neurochem. 2017;140(6):874–88.CrossRefPubMedPubMedCentral
16.
Vatine GD, et al. Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood–brain barrier. Cell Stem Cell. 2017;20(6):p. 831-+.CrossRef
17.
Wang YI, Abaci HE, Shuler ML. Microfluidic blood–brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol Bioeng. 2017;114(1):184–94.CrossRefPubMed
18.
Patel R, Page S, Al-Ahmad AJ. Isogenic blood–brain barrier models based on patient-derived stem cells display inter-individual differences in cell maturation and functionality. J Neurochem. 2017;142(1):74–88.CrossRefPubMed
19.
20.
Hollmann EK, et al. Accelerated differentiation of human induced pluripotent stem cells to blood–brain barrier endothelial cells. Fluids Barriers CNS. 2017;14(1):9.CrossRefPubMedPubMedCentral
21.
Ribecco-Lutkiewicz M, et al. A novel human induced pluripotent stem cell blood–brain barrier model: applicability to study antibody-triggered receptor-mediated transcytosis. Sci Rep. 2018;8:1873.CrossRefPubMedPubMedCentral
22.
Stebbins MJ, et al. Activation of RAR, RAR, or RXR increases barrier tightness in human induced pluripotent stem cell-derived brain endothelial cells. Biotechnol J. 2018;13(2):1700093.CrossRef
23.
Katt ME, et al. Functional brain-specific microvessels from iPSC-derived human brain microvascular endothelial cells: the role of matrix composition on monolayer formation. Fluids Barriers CNS. 2018;15:7.CrossRefPubMedPubMedCentral
24.
Linville RL, et al. Human iPSC-derived blood–brain barrier microvessels: validation of barrier function and endothelial cell behavior. Biomaterials. 2019;190–191:24–37.CrossRefPubMed
25.
Al-Ahmad AJ, et al. Hyaluronan impairs the barrier integrity of brain microvascular endothelial cells through a CD44-dependent pathway. J Cereb Blood Flow Metab. 2018:271678X18767748.
26.
Chiou B, et al. Endothelial cells are critical regulators of iron transport in a model of the human blood–brain barrier. J Cereb Blood Flow Metab. 2018:271678X18783372.
27.
28.
29.
Chou BK, et al. Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Res. 2011;21(3):518–29.CrossRefPubMedPubMedCentral
30.
31.
Neuwelt E, et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 2008;7(1):84–96.CrossRefPubMed
32.
Helms HC, et al. In vitro models of the blood–brain barrier: an overview of commonly used brain endothelial cell culture models and guidelines for their use. J Cereb Blood Flow Metab. 2016;36(5):862–90.CrossRefPubMedPubMedCentral
33.
34.
35.
Bogorad MI, et al. Tissue-engineered 3D microvessel and capillary network models for the study of vascular phenomena. Microcirculation. 2017;24:e12360.CrossRef
36.
Brown JA, et al. Recreating blood–brain barrier physiology and structure on chip: a novel neurovascular microfluidic bioreactor. Biomicrofluidics. 2015;9(5):054124.CrossRefPubMedPubMedCentral
37.
Booth R, Kim H. Characterization of a microfluidic in vitro model of the blood–brain barrier (mu BBB). Lab Chip. 2012;12(10):1784–92.CrossRefPubMed
38.
Yeon JH, et al. Reliable permeability assay system in a microfluidic device mimicking cerebral vasculatures. Biomed Microdevice. 2012;14(6):1141–8.CrossRef
39.
40.
Adriani G, et al. A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood–brain barrier. Lab Chip. 2017;17(3):448–59.CrossRefPubMed
41.
Wevers NR, et al. A perfused human blood–brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport. Fluids Barriers CNS. 2018;15(1):23.CrossRefPubMedPubMedCentral
42.
43.
Herland A, et al. Distinct contributions of astrocytes and pericytes to neuroinflammation identified in a 3D human blood–brain barrier on a chip. PLoS ONE. 2016;11(3):e0150360.CrossRefPubMedPubMedCentral
44.
Partyka PP, et al. Mechanical stress regulates transport in a compliant 3D model of the blood–brain barrier. Biomaterials. 2017;115:30–9.CrossRefPubMed
45.
Campisi M, et al. 3D self-organized microvascular model of the human blood–brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials. 2018;180:117–29.CrossRefPubMedPubMedCentral
46.
Bang S, et al. A low permeability microfluidic blood–brain barrier platform with direct contact between perfusable vascular network and astrocytes. Sci Rep. 2017;7:8083.CrossRefPubMedPubMedCentral
47.
Syvanen S, et al. Species differences in blood–brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos. 2009;37(3):635–43.CrossRefPubMed
48.
Watase K, Zoghbi HY. Modelling brain diseases in mice: the challenges of design and analysis. Nat Rev Genet. 2003;4(4):296–307.CrossRefPubMed
49.
Zlokovic BV. Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci. 2005;28(4):202–8.CrossRefPubMed
50.
51.
Duvernoy H, Delon S, Vannson JL. The vascularization of the human cerebellar cortex. Brain Res Bull. 1983;11(4):419–80.CrossRefPubMed
52.
Schlageter KE, et al. Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc Res. 1999;58(3):312–28.CrossRefPubMed
53.
Risser L, et al. A 3D-investigation shows that angiogenesis in primate cerebral cortex mainly occurs at capillary level. Int J Dev Neurosci. 2009;27(2):185–96.CrossRefPubMed
54.
Risser L, et al. From homogeneous to fractal normal and tumorous microvascular networks in the brain. J Cereb Blood Flow Metab. 2007;27(2):293–303.CrossRefPubMed
55.
Heinzer S, et al. Novel three-dimensional analysis tool for vascular trees indicates complete micro-networks, not single capillaries, as the angiogenic endpoint in mice overexpressing human VEGF(165) in the brain. Neuroimage. 2008;39(4):1549–58.CrossRefPubMed
56.
Meyer EP, et al. Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer’s disease. Proc Natl Acad Sci USA. 2008;105(9):3587–92.CrossRefPubMedPubMedCentral
57.
58.
Abbott NJ, et al. Structure and function of the blood–brain barrier. Neurobiol Dis. 2010;37(1):13–25.CrossRefPubMed
59.
Garcia JH, et al. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol. 1994;144(1):188–99.PubMedPubMedCentral
60.
61.
Kienast Y, et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med. 2010;16(1):116–22.CrossRefPubMed
62.
Larochelle C, Alvarez JI, Prat A. How do immune cells overcome the blood–brain barrier in multiple sclerosis? FEBS Lett. 2011;585(23):3770–80.CrossRefPubMed
63.
Holman DW, Klein RS, Ransohoff RM. The blood–brain barrier, chemokines and multiple sclerosis. Biochim Biophys Acta. 2011;1812(2):220–30.CrossRefPubMed
64.
Takeshita Y, Ransohoff RM. Inflammatory cell trafficking across the blood–brain barrier: chemokine regulation and in vitro models. Immunol Rev. 2012;248:228–39.CrossRefPubMedPubMedCentral
65.
Owens T, Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol. 2008;67(12):1113–21.CrossRefPubMed
66.
Kristensson K, et al. African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions. Prog Neurobiol. 2010;91(2):152–71.CrossRefPubMed
67.
68.
69.
70.
Farkas E, Luiten PGM. Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol. 2001;64(6):575–611.CrossRefPubMed
71.
Nag S. Studies of cerebral vessels by transmission electron microscopy and morphometry. In: Nag S, editor. The blood–brain barrier: biological and research protocols. New York City: Humana Press; 2003. p. 37–50.CrossRef
72.
73.
Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol. 2001;2(4):285–93.CrossRefPubMed
74.
Rodriguez-Baeza A, et al. Perivascular structures in corrosion casts of the human central nervous system: a confocal laser and scanning electron microscope study. Anat Rec. 1998;252(2):176–84.CrossRefPubMed
75.
Wolburg H, Liebner S, Lippoldt A. Freeze-fracture studies of cerebral endothelial tight junctions. Methods Mol Med. 2003;89:51–66.PubMed
76.
DeStefano JG, et al. Real-time quantification of endothelial response to shear stress and vascular modulators. Integr Biol. 2017;9(4):362–74.CrossRef
77.
78.
79.
Garcia-Polite F, et al. Pulsatility and high shear stress deteriorate barrier phenotype in brain microvascular endothelium. J Cereb Blood Flow Metab. 2017;37(7):2614–25.CrossRefPubMed
80.
81.
Dolan JM, Kolega J, Meng H. High wall shear stress and spatial gradients in vascular pathology: a review. Ann Biomed Eng. 2013;41(7):1411–27.CrossRefPubMed
82.
Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA. 1999;282(21):2035–42.CrossRefPubMed
83.
84.
Gould IG, et al. The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. J Cereb Blood Flow Metab. 2017;37(1):52–68.CrossRefPubMed
85.
Kleinfeld D, et al. Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc Natl Acad Sci. 1998;95(26):15741–6.CrossRefPubMedPubMedCentral
86.
87.
Unekawa M, et al. RBC velocities in single capillaries of mouse and rat brains are the same, despite 10-fold difference in body size. Brain Res. 2010;1320:69–73.CrossRefPubMed
88.
Hudetz AG. Blood flow in the cerebral capillary network: a review emphasizing observations with intravital microscopy. Microcirculation. 1997;4(2):233–52.CrossRefPubMed
89.
Villringer A, et al. Capillary perfusion of the rat brain cortex. An in vivo confocal microscopy study. Circ Res. 1994;75(1):55–62.CrossRefPubMed
90.
Ivanov K, Kalinina M, Levkovich YI. Blood flow velocity in capillaries of brain and muscles and its physiological significance. Microvasc Res. 1981;22(2):143–55.CrossRefPubMed
91.
Ma Y, et al. On-line measurement of the dynamic velocity of erythrocytes in the cerebral microvessels in the rat. Microvasc Res. 1974;8(1):1–13.CrossRefPubMed
92.
Turitto VT. Blood viscosity, mass transport, and thrombogenesis. Prog Hemost Thromb. 1982;6:139–77.PubMed
93.
Drake CT, Iadecola C. The role of neuronal signaling in controlling cerebral blood flow. Brain Lang. 2007;102(2):141–52.CrossRefPubMed
94.
Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol. 2006;100(1):328–35.CrossRefPubMed
95.
Lauritzen M. Relationship of spikes, synaptic activity, and local changes of cerebral blood flow. J Cereb Blood Flow Metab. 2001;21(12):1367–83.CrossRefPubMed
96.
97.
Chen BR, et al. High-speed vascular dynamics of the hemodynamic response. Neuroimage. 2011;54(2):1021–30.CrossRefPubMed
98.
Shih AY, et al. Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain. J Cereb Blood Flow Metab. 2012;32(7):1277–309.CrossRefPubMedPubMedCentral
99.
Koutsiaris AG, et al. Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo. Biorheology. 2007;44(5–6):375–86.PubMed
100.
Santisakultarm TP, et al. In vivo two-photon excited fluorescence microscopy reveals cardiac- and respiration-dependent pulsatile blood flow in cortical blood vessels in mice. Am J Physiol Heart Circ Physiol. 2012;302(7):H1367–77.CrossRefPubMedPubMedCentral
101.
Errico C, et al. Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. Nature. 2015;527(7579):499.CrossRefPubMed
102.
Gangoda SVS, et al. Pulsatile stretch as a novel modulator of amyloid precursor protein processing and associated inflammatory markers in human cerebral endothelial cells. Sci Rep. 2018;8(1):1689.CrossRefPubMedPubMedCentral
103.
104.
Tilling T, et al. Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cell cultures. Cell Tissue Res. 2002;310(1):19–29.CrossRefPubMed
105.
Tilling T, et al. Basement membrane proteins influence brain capillary endothelial barrier function in vitro. J Neurochem. 1998;71(3):1151–7.CrossRefPubMed
106.
Hartmann C, et al. The impact of glia-derived extracellular matrices on the barrier function of cerebral endothelial cells: an in vitro study. Exp Cell Res. 2007;313(7):1318–25.CrossRefPubMed
107.
108.
Iozzo RV, et al. The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J. 1994;302(Pt 3):625.CrossRefPubMedPubMedCentral
109.
110.
Dermietzel R, Krause D. Molecular anatomy of the blood–brain-barrier as defined by immunocytochemistry. Int Rev Cytol. 1991;127:57–109.CrossRefPubMed
111.
112.
113.
Thorne RG, Nicholson C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci USA. 2006;103(14):5567–72.CrossRefPubMedPubMedCentral
114.
Thorne RG, Hrabetova S, Nicholson C. Diffusion measurements for drug design. Nat Mater. 2005;4(10):713.CrossRefPubMed
115.
Kroeger D, et al. Activity-dependent layer-specific changes in the extracellular chloride concentration and chloride driving force in the rat hippocampus. J Neurophysiol. 2010;103(4):1905–14.CrossRefPubMed
116.
Zimmermann DR, Dours-Zimmermann MT. Extracellular matrix of the central nervous system: from neglect to challenge. Histochem Cell Biol. 2008;130(4):635–53.CrossRefPubMed
117.
Yamaguchi Y. Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci. 2000;57(2):276–89.CrossRefPubMed
118.
Sanes JR. Extracellular-matrix molecules that influence neural development. Annu Rev Neurosci. 1989;12:491–516.CrossRefPubMed
119.
Luissint AC, et al. Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS. 2012;9(1):23.CrossRefPubMedPubMedCentral
120.
Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev Mol Cell Biol. 2003;4(3):225–36.CrossRefPubMed
121.
122.
Ohtsuki S, et al. mRNA expression levels of tight junction protein genes in mouse brain capillary endothelial cells highly purified by magnetic cell sorting. J Neurochem. 2008;104(1):147–54.PubMed
123.
Weksler BB, et al. Blood–brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J. 2005;19(13):1872–4.CrossRefPubMed
124.
Bernas MJ, et al. Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood–brain barrier. Nat Protoc. 2010;5(7):1265–72.CrossRefPubMedPubMedCentral
125.
Goodall EF, et al. Age-associated changes in the blood–brain barrier: comparative studies in human and mouse. Neuropathol Appl Neurobiol. 2018;44(3):328–40.CrossRefPubMed
126.
Errede M, et al. The contribution of CXCL12-expressing radial glia cells to neuro-vascular patterning during human cerebral cortex development. Front Neurosci. 2014;8:324.CrossRefPubMedPubMedCentral
127.
Gaillard PJ, de Boer AG. Relationship between permeability status of the blood–brain barrier and in vitro permeability coefficient of a drug. Eur J Pharm Sci. 2000;12(2):95–102.CrossRefPubMed
128.
Crone C, Olesen SP. Electrical resistance of brain microvascular endothelium. Brain Res. 1982;241(1):49–55.CrossRefPubMed
129.
Butt AM, Jones HC, Abbott NJ. Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study. J Physiol. 1990;429:47–62.CrossRefPubMedPubMedCentral
130.
Butt AM, Jones HC. Effect of histamine and antagonists on electrical-resistance across the blood–brain-barrier in rat brain-surface microvessels. Brain Res. 1992;569(1):100–5.CrossRefPubMed
131.
Smith QR, Rapoport SI. Cerebrovascular permeability coefficients to sodium, potassium, and chloride. J Neurochem. 1986;46(6):1732–42.CrossRefPubMed
132.
Eigenmann DE, et al. Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood–brain barrier model for drug permeability studies. Fluids Barriers CNS. 2013;10(1):33.CrossRefPubMedPubMedCentral
133.
Daniels BP, et al. Immortalized human cerebral microvascular endothelial cells maintain the properties of primary cells in an in vitro model of immune migration across the blood brain barrier. J Neurosci Methods. 2013;212(1):173–9.CrossRefPubMed
134.
Khan NA. Novel in vitro and in vivo models to study central nervous system infections due to Acanthamoeba spp. Exp Parasitol. 2010;126(1):69–72.CrossRefPubMed
135.
Saunders NR, et al. The rights and wrongs of blood–brain barrier permeability studies: a walk through 100 years of history. Front Neurosci. 2014;8:404.CrossRefPubMedPubMedCentral
136.
Ribatti D, et al. Development of the blood–brain barrier: a historical point of view. Anat Rec B New Anat. 2006;289(1):3–8.CrossRefPubMed
137.
138.
Jeong JY, et al. Functional and developmental analysis of the blood–brain barrier in zebrafish. Brain Res Bull. 2008;75(5):619–28.CrossRefPubMed
139.
Yuan W, et al. Non-invasive measurement of solute permeability in cerebral microvessels of the rat. Microvasc Res. 2009;77(2):166–73.CrossRefPubMed
140.
Shi L, et al. Quantification of blood–brain barrier solute permeability and brain transport by multiphoton microscopy. J Biomech Eng. 2014;136(3):031005.CrossRefPubMed
141.
Nag S. Blood–brain barrier permeability using tracers and immunohistochemistry. In: Nag S, editor. The blood–brain barrier: biological and research protocols. New York City: Humana Press; 2003. p. 133–44.CrossRef
142.
Honig G, et al. Blood–brain barrier deterioration and hippocampal gene expression in polymicrobial sepsis: an evaluation of endothelial MyD88 and the vagus nerve. PLoS ONE. 2016;11(1):e0144215.CrossRefPubMedPubMedCentral
143.
Wulkersdorfer B, et al. Using positron emission tomography to study transporter-mediated drug–drug interactions in tissues. Clin Pharmacol Ther. 2014;96(2):206–13.CrossRefPubMedPubMedCentral
144.
Dauchy S, et al. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood–brain barrier. J Neurochem. 2008;107(6):1518–28.CrossRefPubMed
145.
Ohtsuki S, Terasaki T. Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; Importance for CNS drug discovery and development. Pharm Res. 2007;24(9):1745–58.CrossRefPubMed
146.
Summerfield SG, et al. Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction. J Pharmacol Exp Ther. 2007;322(1):205–13.CrossRefPubMed
147.
Bauer M, et al. Approaching complete inhibition of P-glycoprotein at the human blood–brain barrier: an (R)-[11C]verapamil PET study. J Cereb Blood Flow Metab. 2015;35(5):743–6.CrossRefPubMedPubMedCentral
148.
Polli JW, et al. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos. 2009;37(2):439–42.CrossRefPubMed
149.
150.
Spaet TH, Lejnieks I. Mitotic activity of rabbit blood vessels. Proc Soc Exp Biol Med. 1967;125(4):1197–201.CrossRefPubMed
151.
Tannock IF, Hayashi S. The proliferation of capillary endothelial cells. Cancer Res. 1972;32(1):77–82.PubMed
152.
Cudmore RH, Dougherty SE, Linden DJ. Cerebral vascular structure in the motor cortex of adult mice is stable and is not altered by voluntary exercise (vol 37, pg 3725, 2017). J Cereb Blood Flow Metab. 2017;37(12):3824.CrossRef
153.
Harb R, et al. In vivo imaging of cerebral microvascular plasticity from birth to death. J Cereb Blood Flow Metab. 2013;33(1):146–56.CrossRefPubMed
154.
Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10(11):1369–76.CrossRefPubMed
155.
156.
Figley CR, Stroman PW. The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals. Eur J Neurosci. 2011;33(4):577–88.CrossRefPubMed
157.
Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.CrossRefPubMed
158.
159.
Mathiisen TM, et al. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia. 2010;58(9):1094–103.CrossRefPubMed
160.
Ridet JL, et al. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1997;20(12):570–7.CrossRefPubMed
161.
162.
163.
164.
Placone AL, Quinones-Hinojosa A, Searson PC. The role of astrocytes in the progression of brain cancer: complicating the picture of the tumor microenvironment. Tumour Biol. 2016;37(1):61–9.CrossRefPubMed
165.
Puschmann TB, et al. Bioactive 3D cell culture system minimizes cellular stress and maintains the in vivo-like morphological complexity of astroglial cells. Glia. 2013;61(3):432–40.CrossRefPubMed
166.
167.
Wolburg H, Lippoldt A. Tight junctions of the blood–brain barrier: development, composition and regulation. Vasc Pharmacol. 2002;38(6):323–37.CrossRef
168.
Nicchia GP, et al. The role of aquaporin-4 in the blood–brain barrier development and integrity: studies in animal and cell culture models. Neuroscience. 2004;129(4):935–45.CrossRefPubMed
169.
Levy AF, et al. Influence of basement membrane proteins and endothelial cell-derived factors on the morphology of human fetal-derived astrocytes in 2D. PLoS ONE. 2014;9(3):e92165.CrossRefPubMedPubMedCentral
170.
Placone AL, et al. Human astrocytes develop physiological morphology and remain quiescent in a novel 3D matrix. Biomaterials. 2015;42:134–43.CrossRefPubMed
171.
Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21(2):193–215.CrossRefPubMed
172.
Hartmann DA, et al. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics. 2015;2(4):041402.CrossRefPubMedPubMedCentral
173.
Hill RA, et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron. 2015;87(1):95–110.CrossRefPubMedPubMedCentral
174.
Damisah EC, et al. A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging. Nat Neurosci. 2017;20(7):p. 1023-+.CrossRef
175.
176.
177.
Frank RN, Dutta S, Mancini MA. Pericyte coverage is greater in the retinal than in the cerebral capillaries of the rat. Invest Ophthalmol Vis Sci. 1987;28(7):1086–91.PubMed
178.
179.
180.
Crisan M, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301–13.CrossRefPubMed
181.
Dore-Duffy P. Pericytes: pluripotent cells of the blood brain barrier. Curr Pharm Des. 2008;14(16):1581–93.CrossRefPubMed
182.
Correa D, et al. Mesenchymal stem cells regulate melanoma cancer cells extravasation to bone and liver at their perivascular niche. Int J Cancer. 2016;138(2):417–27.CrossRefPubMed
183.
Blocki A, et al. Not all MSCs can act as pericytes: functional in vitro assays to distinguish pericytes from other mesenchymal stem cells in angiogenesis. Stem Cells Dev. 2013;22(17):2347–55.CrossRefPubMedPubMedCentral
184.
185.
Gerhardt H, Betsholtz C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 2003;314(1):15–23.CrossRefPubMed
186.
187.
188.
Hayashi K, et al. Effects of hypoxia on endothelial/pericytic co-culture model of the blood–brain barrier. Regul Pept. 2004;123(1):77–83.CrossRefPubMed
189.
Nakagawa S, et al. A new blood–brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int. 2009;54(3–4):253–63.CrossRefPubMed
190.
Nakagawa S, et al. Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol. 2007;27(6):687–94.CrossRefPubMed
191.
Siddharthan V, et al. Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells. Brain Res. 2007;1147:39–50.CrossRefPubMedPubMedCentral
192.
Thomsen LB, Burkhart A, Moos T. A triple culture model of the blood–brain barrier using porcine brain endothelial cells, astrocytes and pericytes. PLoS ONE. 2015;10(8):e0134765.CrossRefPubMedPubMedCentral
193.
Malina KCK, Cooper I, Teichberg VI. Closing the gap between the in vivo and in vitro blood–brain barrier tightness. Brain Res. 2009;1284:12–21.CrossRef
194.
Yang T, Roder KE, Abbruscato TJ. Evaluation of bEnd5 cell line as an in vitro model for the blood–brain barrier under normal and hypoxic/aglycemic conditions. J Pharm Sci. 2007;96(12):3196–213.CrossRefPubMed
195.
Hatherell K, et al. Development of a three-dimensional, all-human in vitro model of the blood–brain barrier using mono-, co-, and tri-cultivation transwell models. J Neurosci Methods. 2011;199(2):223–9.CrossRefPubMed
196.
Hori S, et al. A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem. 2004;89(2):503–13.CrossRefPubMed
197.
Weksler BB, et al. Blood–brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J. 2005;19(11):1872–4.CrossRefPubMed
198.
Thanabalasundaram G, et al. Regulation of the blood–brain barrier integrity by pericytes via matrix metalloproteinases mediated activation of vascular endothelial growth factor in vitro. Brain Res. 2010;1347:1–10.CrossRefPubMed
199.
Thanabalasundaram G, et al. The impact of pericytes on the blood–brain barrier integrity depends critically on the pericyte differentiation stage. Int J Biochem Cell Biol. 2011;43(9):1284–93.CrossRefPubMed
200.
Lippmann ES, et al. Blood–brain barrier modeling with co-cultured neural progenitor cell-derived astrocytes and neurons. J Neurochem. 2011;119(3):507–20.CrossRefPubMedPubMedCentral
201.
Thomsen LB, Burkhart A, Moos T. A triple culture model of the blood–brain barrier using porcine brain endothelial cells, astrocytes and pericytes. PLoS ONE. 2015;10(8):1–16.CrossRef
202.
203.
Vanlandewijck M, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554(7693):475–80.CrossRefPubMed
204.
Linville RM, et al. Physical and chemical signals that promote vascularization of capillary-scale channels. Cell Mol Bioeng. 2016;9(1):73–84.CrossRefPubMed
205.
Maoz BM, et al. A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells. Nat Biotechnol. 2018;36(9):865–74.CrossRefPubMed
206.
Park J, et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci. 2018;21(7):941–51.CrossRefPubMedPubMedCentral
Metadata
Title
Benchmarking in vitro tissue-engineered blood–brain barrier models
Authors
Jackson G. DeStefano
John J. Jamieson
Raleigh M. Linville
Peter C. Searson
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Fluids and Barriers of the CNS / Issue 1/2018
Electronic ISSN: 2045-8118
DOI
https://doi.org/10.1186/s12987-018-0117-2

Other articles of this Issue 1/2018

Fluids and Barriers of the CNS 1/2018 Go to the issue

Research

Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

Research

Pulsatile flow drivers in brain parenchyma and perivascular spaces: a resistance network model study

Review

Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers

Research

Accurate, strong, and stable reporting of choroid plexus epithelial cells in transgenic mice using a human transthyretin BAC

Review

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Research

Role of cationic drug-sensitive transport systems at the blood-cerebrospinal fluid barrier in para-tyramine elimination from rat brain