Blood-brain barrier models in vitro: current situation and prospects

Cover Page


Cite item

Full Text

Abstract

Current experimental models of the blood-brain barrier (BBB) in vitro used for studying mechanisms of permeability and intercellular communication are discussed in this review. At present, monolayer, multilayer and computer models are in use for the above-mentioned purposes. Primary isolated cells that make up the models in vitro may have brain and non-brain origin. In addition, transplantable cell lines and co-cultured cells could be used for modeling BBB in vitro.

 
 

About the authors

A. V. Morgun

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

N. V. Kuvacheva

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

Yu. K. Kоmleva

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

E. A. Pozhilenkova

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

I. A. Kutishcheva

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

E. S. Gagarina

Krasnoyarsk State Medical University

Author for correspondence.
Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

T. E. Taranushenko

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

A. V. Ozerskaya

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

O. S. Okuneva

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

A. B. Salmina

Krasnoyarsk State Medical University

Email: Ximikat-007@yandex.ru
Russian Federation, Krasnoyarsk

References

  1. Aasmundstad T.A., Morland J., Paulsen R.E. Distribution of morphine 6-glucuronide and morphine across the blood-brain barrier in awake, freely moving rats investigated by in vivo microdialysis sampling. J. Pharmacol. Exp. Ther. 1995; 275: 435–441.
  2. Abbott N.J. Astrocyte-endothelial interactions and blood-brain barrier permeability. J. Anat. 2002; 200: 629–638.
  3. Abbott N.J., Rönnbäck L., Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 2006; 7: 41–53.
  4. Andersson P.B., Perry V.H., Gordon S. The acute inflammatory response to lipopolysaccharide in central nervous system parenchyma differs from that in other body tissues. Neuroscience. 1992; 48: 169–186.
  5. Armulik A., Genové G., Mäe M. et al. Pericytes regulate the bloodbrain barrier. Nature. 2010; 468: 557–561.
  6. Arthur F.E., Shivers R.R., Bowman P.D. Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model. Brain Research. 1987; 433: 155–159.
  7. Ballabh P., Braun A., Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol. Dis. 2004; 16: 1–13.
  8. Begley D.J. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities.Pharmacol Ther. 2004; 104: 29–45.
  9. Berezowski V., Landry C., Dehouck M.P. et al. Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistance-associated proteins in an in vitro model of the bloodbrain barrier. Brain Res. 2004; 1018: 1–9.
  10. Bernas M.J., Cardoso F.L., Daley S.K. 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. 2005; 5: 1265–1272.
  11. Bickel U. How to measure drug transport across the blood-brain barrier. Neuro Rx. 2005; 2: 15–26.
  12. Bonate P.L. Animal models for studying transport across the bloodbrain barrier. J. Neurosci. Methods. 1995; 56: 1–15.
  13. Bradbury M.W. The blood-brain barrier: transport across the cerebral endothelium. Circ. Res. 1985; 57: 213–222.
  14. Braun A., Hammerle S., Suda K. et al. Cell cultures as tools in biopharmacy. Eur. J. Pharm. Sci. 2000; 11: 51–60.
  15. Carl S.M., Lindley D.J., Couraud P.O. et al. ABC and SLC transporter expression and pot substrate characterization across the human CMEC/D3 blood-brain barrier cell line. Mol. Pharm. 2010; 7: 1057–1068.
  16. Cestelli A., Catania C., D’Agostino S. et al. Functional feature of a novel model of blood brain barrier: studies on permeation of test compounds. J. Control Release. 2001; 76: 139–147.
  17. Cohen-Kashi Malina K., Cooper I., Teichberg V.I. Closing the gap between the in-vivo and in-vitro blood-brain barrier tightness. Brain Res. 2009; 1284: 12–21.
  18. Cucullo L., Couraud P.O., Weksler B. et al. Immortalized human brain endothelial cells and flow-based vascular modeling: a marriage of convenience for rational neurovascular studies. J. Cereb. Blood Flow Metab. 2008; 28: 312–328.
  19. Cucullo L., McAllister M.S., Kight K. A new dynamic in vitro model for the multidimensional study of astrocyte-endothelial cell interactions at the blood-brain barrier. Brain Res. 2002; 951: 243–254.
  20. Culot M., Lundquist S., Vanuxeem D. et al. An in vitro blood-brain barrier model for high throughput (HTS) toxicological screening. Toxicol. In Vitro 2008; 22: 799–811.
  21. Dauchy S., Miller F., Couraud P.O. Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells. Biochem. Pharmacol. 2009; 77: 897–909.
  22. Dе Vries H.E., Kuiper J., De Boer A.G. et al. The blood-brain barrier in neuroinflammatory diseases. Pharmacol. Rev. 1997; 49: 143.
  23. DeBault L.E., Cancilla P.A. Gamma-Glutamyl transpeptidase in isolated brain endothelial cells: induction by glial cells in vitro. Science. 1980; 207: 653–655.
  24. DeBault L.E., Henriquez E., Hart M.N., Cancilla P.A. Cerebral microvessels and derived cells in tissue culture: II. Establishment, identification, and preliminary characterization of an endothelial cell line. In Vitro 1981; 17: 480–494
  25. DeBault L.E., Kahn L.E., Frommes S.P., Cancilla P.A. Cerebral microvessels and derived cells in tissue culture: isolation and preliminary characterization. In Vitro 1979; 15: 473–487.
  26. Dehouck M.P., Méresse S., Delorme P. et al. An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J. Neurochem. 1990; 54: 1798–1801.
  27. Dehouck M.P., Vigne P., Torpier G. et al. Endothelin-1 as a mediator of endothelial cell-pericyte interactions in bovine brain capillaries. J. Cereb. Blood Flow Metab. 1997; 17: 464–469.
  28. Del Zoppo G.J., Hallenbeck J.M. Advances in the vascular pathophysiology of ischemic stroke. Thromb. Res. 2000; 98: 73–81.
  29. Deli M.A., Abrahám C.S., Kataoka Y., Niwa M. Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol. Neurobiol. 2005; 25: 59–127.
  30. Deli M.A., Abrahám C.S., Niwa M., Falus A. N,N-diethyl-2-[4- (phenylmethyl)phenoxy]ethanamine increases the permeability of primary mouse cerebral endothelial cell monolayers. Inflamm. Res. 2003; 52: 39 – 40.
  31. Deli M.A., Abrahám C.S., Takahata H., Niwa M. Tissue plasminogen activator inhibits P-glycoprotein activity in brain endothelial cells. Eur. J. Pharmacol. 2001; 411: 3–5.
  32. Dohgu S., Takata F., Yamauchi A. et al. Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res. 2005; 1038: 208–215.
  33. Dore-Duffy P. Pericytes: pluripotent cells of the blood brain barrier. Curr. Pharm. Des. 2008; 14: 1581–1593.
  34. Fenstermacher J., Gross P., Sposito N. et al. Structural and functional variations in capillary systems within the brain. Ann. N.Y. Acad. Sci. 1988; 529: 21–30.
  35. Fischer S., Nishio M., Peters S.C. Signaling mechanism of extracellular RNA in endothelial cells. FASEB. 2009; 23: 2100–2109.
  36. Goodwin J.T., Clark D.E. In silico predictions of blood-brain barrier penetration: considerations to «keep in mind». J. Pharmacol. Exp. Ther. 2005; 315: 477–483.
  37. Greenwood J., Pryce G., Devine L. et al. SV40 large T immortalised cell lines of the rat blood-brain and blood-retinal barriers retain their phenotypic and immunological characteristics. J. Neuroimmunol. 1996; 71: 51–63.
  38. Gumbleton M., Audus K.L. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier. J. Pharm. Sci. 2001; 90: 1681–1698.
  39. Hafler D.A., Weiner H. L. T-cells in multiple sclerosis and inflammatory central nervous system diseases. Immunol. Rev. 1987; 100: 307–332.
  40. Hawkins B.T., Davis T.P. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 2005; 57: 173–185.
  41. Hayashi K., Nakao S., Nakaoke R. Effects of hypoxia on endothelial/ pericytic co-culture model of the blood-brain barrier. Regul. Pept. 2004; 123: 77–83.
  42. Hori S., Ohtsuki S., Hosoya K. 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: 503–513.
  43. Hu J.G., Wang X.F., Zhou J.S. et al. Activation of PKC-alpha is required for migration of C6 glioma cells. Acta Neurobiol. Exp. 2010; 70: 239–245.
  44. Hutamekalin P., Farkas A.E., Orbók A. et al. Effect of nicotine and polyaromtic hydrocarbons on cerebral endothelial cells. Cell Biol. Int. 2008; 32: 198–209.
  45. Janzer R.C., Raff M.C. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987; 325: 253–257.
  46. Juhler M., Blasberg R.G,. Fenstermacher J.D. et al. A spatial analysis of the blood-brain barrier damage in experimental allergic encephalomyelitis. J. Cereb. Blood Flow Metab. 1985; 5: 545–553.
  47. Kniesel U., Wolburg H. Tight junctions of the blood-brain barrier. Cell. Mol. Neurobiol. 2000; 20: 57–76.
  48. Langford D., Hurford R., Hashimoto M. et al. Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120. BMC Neurosci. 2005; 6: 8–23.
  49. Lassmann H., Zimprich F., Rössler K., Vass K. Inflammation in the nervous system. Basic mechanisms and immunological concepts. Rev. Neurol. 1991; 147: 763–781.
  50. Lee H.T., Chang Y.C., Tu Y.F., Huang C.C. CREB activation mediates VEGF-A’s protection of neurons and cerebral vascular endothelial cells. J. Neurochem. 2010; 113: 79–91.
  51. Lim J.C., Kania K.D., Wijesuriya H. et al. Activation of beta-catenin signalling by GSK-3 inhibition increases P-glycoprotein expression in brain endothelial cells. J. Neurochem. 2008; 106: 1855–1865.
  52. Lupo G., Nicotra A., Giurdanella G. et al. Activation of phospholipase A(2) and MAP kinases by oxidized low-density lipoproteins in immortalized GP8.39 endothelial cells. Biochim. Biophys. Acta 2005; 1735: 135–150.
  53. Mahar-Doan K.M., Humphreys J.E., Webster L.O. et al. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther. 2002; 303: 1029–103.
  54. Mamo D., Remington G., Nobrega J. et al. Effect of acute antipsychotic administration on dopamine synthesis in rodents and human subjects using 6-[18F]-l-m-tyrosine. Synapse 2004; 52: 153–162.
  55. Mater S., Maickel R.P., Brodie B.B. Kinetics of penetration of drugs and other foreign compounds into cerebrospinal fluid and brain. J. Pharmacol. Exp. Ther. 1959; 127: 205–211.
  56. Megard I., Garrigues A., Orlowski S. et al. A co-culture-based model of human blood-brain barrier: application to active transport of indinavir and in vivo-in vitro correlation. Brain Res. 2002; 927: 153–167.
  57. Nakagawa S., Deli M.A., Kawaguchi H. et al. A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem. Int. 2009; 54: 253–263.
  58. Nakagawa S., Deli M.A., Nakao S. et al. Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol. Neurobiol. 2007; 27: 687–694.
  59. Nazer B., Hong S., Selkoe D.J. LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model. Neurobiol. Dis. 2008; 30: 94–102.
  60. Nedergaard M., Ransom B., Goldman S.A. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 2003; 26: 523–530.
  61. Neuhaus W., Lauer R., Oelzant S. et al. A novel flow based hollowfiber blood-brain barrier in vitro model with immortalised cell line PBMEC/C1-2. J. Biotechnol. 2006; 125: 127–141.
  62. Oldendorf W. H. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res. 1970; 24: 372–376.
  63. Oldendorf W.H., Cornford M.E., Brown W.J. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann. Neurol. 1977; 1: 409–417.
  64. Oldendorf W.H., Pardridge W.M., Braun, L.D., Crane P.D. Measurement of cerebral glucose utilization using washout after carotid injection in the rat. J. Neurochem. 1982; 38: 1413–1418.
  65. Panula P., Joó F., Rechardt L. Evidence for the presence of viable endothelial cells in cultures derived from dissociated rat brain. Experientia 1978; 34: 95–97.
  66. Peppiatt C.M., Howarth C., Mobbs P., Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature 2006; 443: 700–704.
  67. Persidsky Y., Stins M., Way D. et al. A model for monocyte migration through the blood-brain barrier during HIV-1 encephalitis. J. of Immun. 1997; 158: 3499–3510.
  68. Rapoport S.I., Ohno K., Pettigrew K.D. Drug entry into the brain. Brain Res. 1979; 172: 354–359.
  69. Raub T.J. Signal transduction and glial cell modulation of cultured brain microvessel endothelial cell tight junctions. Am. J. Physiol. 1996; 271: 495–503
  70. Régina A., Koman A., Piciotti M. et al. Mrp1 multidrug resistanceassociated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. J. Neurochem. 1998;
  71. –715
  72. Régina A., Romero I.A., Greenwood J. et al. Dexamethasone regulation of P-glycoprotein activity in an immortalized rat brain endothelial cell line, GPNT. J. Neurochem. 1999; 73: 1954–1963.
  73. Roux F., Durieu-Trautmann O., Chaverot N. et al. Regulation of gamma-glutamyl-transpeptidase and alkaline phosphatase activities in immortalized rat brain microvessel endothelial cells. J. Cell. Physiol. 1994; 159: 101–113.
  74. Rubin L.L., Hall D.E., Porter S. et al. A cell culture model of the blood-brain barrier. J. Cell Biol. 1991; 115: 1725–1735.
  75. Rubino E., Rainero I., Vaula G. et al. Investigating the genetic role of aquaporin4 gene in migraine. J. Headache Pain 2009; 10: 111–114.
  76. Sano Y., Shimizu F., Abe M. et al. Establishment of a new conditionally immortalized human brain microvascular endothelial cell line retaining an in vivo blood-brain barrier function. J. Cell. Physiol. 2010; 225: 519–528.
  77. Schreibelt G., Kooij G., Reijerkerk A. et al. Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling. FASEB. 2007; 21: 3666–3676.
  78. Sedlakova R., Shivers R.R., Del Maestro R.F. Ultrastructure of the blood-brain barrier in the rabbit. J. Submicrosc. Cytol. Pathol. 1999; 31: 149–161.
  79. Siddharthan V., Kim Y.V., Liu S., Kim K.S. Human astrocytes/astrocyte- conditioned medium and shear stress enhance the barrier properties of human brain microvas cular endothelial cells. Brain Res. 2007; 1147: 39–50.
  80. Smith M., Omidi Y., Gumbleton M. Primary porcine brain microvascular endothelial cells: biochemical and functional characterisation as a model for drug transport and targeting. J. Drug Target 2007; 15: 253–268.
  81. Sobue K., Yamamoto N., Yoneda K. et al. Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci. Res. 1999; 35: 155–164.
  82. Stamatovic S.M., Shakui P., Keep R.F. et al. Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability. J. Cereb. Blood Flow Metab. 2005; 25: 593–606.
  83. Stanness K.A., Westrum L.E., Fornaciari E. Morphological and functional characterization of an in vitro blood-brain barrier model. Brain Res. 1997; 771: 329–342.
  84. Stewart P.A., Wiley M.J. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: A study using quail-chick transplantation chimeras. Develop. Biol. 1981; 183–192.
  85. Takano T., Tian G.F., Peng W. et al. Astrocyte-mediated control of cerebral blood flow. Nat. Neurosci. 2006; 9: 260–267.
  86. Tarbell J.M. Shear stress and the endothelial transport barrier. Cardiovasc. Res. 2010; 87: 320–330.
  87. Tontsch U., Bauer H.C. Glial cells and neurons induce blood-brain barrier related enzymes in cultured cerebral endothelial cells. Brain Res. 1991; 539: 247–253.
  88. Van Bree J.B., De Boer A.G., Danhof M. et al. Characterization of an «in vitro» blood-brain barrier: effects of molecular size and lipophilicity on cerebrovascular endothelial transport rates of drugs. J. Pharmacol. Exp. Ther. 1988; 247: 1233–1239.
  89. Vandamme W., Braet K., Cabooter L., Leybaert L. Tumour necrosis factor alpha inhibits purinergic calcium signalling in blood-brain barrier endothelial cells. J. Neurochem. 2004; 88: 411–421.
  90. Veszelka S., Pásztói M., Farkas A.E. et al. Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharideinduced damages. Neurochem. Int. 2007; 50: 219–228.
  91. Wang Q., Rager J.D., Weinstein K. et al. Evaluation of the MDRMDCK cell line as a permeability screen for the blood-brain barrier. Int. J. of Pharm. 2005; 288: 349–359.
  92. Webb S., Ott R.J., Cherry S.R. Quantitation of blood-brain barrier permeability by positron emission tomography. Phys. Med. Biol. 1989; 34: 1767–1771.
  93. Weidenfeller C., Svendsen C.N., Shusta E.V. Differentiating embryonic neural progenitor cells induce blood-brain barrier properties. J. Neurochem. 2007; 101: 555–565.
  94. Wekerle H., Schwab M., Linington C., Meyermann R. Antigen presentation in the peripheral nervous system: Schwann cells present endogenous myelin autoantigens to lymphocytes. Eur. J. Immunol. 1986; 16: 1551–1557.
  95. Weksler B.B., Subileau E.A., Perrière N. et al. Blood-brain barrierspecific properties of a human adult brain endothelial cell line. FASEB. 2005; 19: 1872–1874.
  96. Westergren I., Nystrom B., Hamberger A., Johansson B.B. Intracerebral dialysis and the blood-brain barrier. J. Neurochem. 1995; 64: 229–234.
  97. Wilhelm I., Fazakas C., Krizbai I.A. In vitro models of the bloodbrain barrier Acta Neurobiol. Exp. 2011; 71: 113–128.
  98. Wilhelm I., Nagyoszi P., Farkas A.E. et al. Hyperosmotic stress induces Axl activation and cleavage in cerebral endothelial cells. J. Neurochem. 2008; 107: 116–126.
  99. Zastre J.A., Chan G.N., Ronaldson P.T. Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. J. Neurosci. Res. 2009; 87: 1023–1036.
  100. Zhong Y., Smart E.J., Weksler B. et al. Caveolin-1 regulates human immunodeficiency virus-1 Tat-induced alterations of tight junction protein expression via modulation of the Ras signaling. J. Neurosci. 2008; 28: 7788–7796.
  101. Zonta M., Angulo M.C., Gobbo S., et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 2003; 6: 43–50.
  102. Zozulya A., Weidenfeller C., Galla H.J. Pericyte-endothelial cell interaction increases MMP-9 secretion at the blood-brain barrier in vitro. Brain Res. 2008; 1189: 1–11.
  103. Zysk G., Schneider-Wald B.K., Hwang J.H. Pneumolysin is the main inducer of cytotoxicity to brain microvascular endothelial cells caused by Streptococcus pneumoniae. Infect. Immun. 2001; 69: 845–852.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2012 Morgun A.V., Kuvacheva N.V., Kоmleva Y.K., Pozhilenkova E.A., Kutishcheva I.A., Gagarina E.S., Taranushenko T.E., Ozerskaya A.V., Okuneva O.S., Salmina A.B.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-83204 от 12.05.2022.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies