Abstract
The blood–brain barrier (BBB) is a component of the neurovascular unit formed by specialized brain microvascular endothelial cells surrounded by astrocytes end-feet processes, pericytes, and a basement membrane. The BBB plays an important role in the maintenance of brain homeostasis and has seen a growing involvement in the pathophysiology of various neurological diseases. On the other hand, the presence of such a barrier remains an important challenge for drug delivery to treat such illnesses.
Since the pioneering work describing the isolation and cultivation of primary brain microvascular cells about 50 years ago until now, the development of an in vitro model of the BBB that is scalable, capable to form tight monolayers, and predictive of drug permeability in vivo remained extremely challenging.
The recent description of the use of induced pluripotent stem cells (iPSCs) as a modeling tool for neurological diseases raised momentum into the use of such cells to develop new in vitro models of the BBB. This chapter will provide an exhaustive description of the use of iPSCs as a source of cells for modeling the BBB in vitro, describe the advantages and limitations of such model, as well as describe their prospective use for disease modeling and drug permeability screening platforms.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Joo F, Karnushina I (1973) A procedure for the isolation of capillaries from rat brain. Cytobios 8(29):41–48
Jackson S, Meeks C, Vezina A et al (2019) Model systems for studying the blood-brain barrier: applications and challenges. Biomaterials 214:119217. https://doi.org/10.1016/j.biomaterials.2019.05.028
Helms HC, Abbott NJ, Burek M et al (2016) 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 36(5):862–890. https://doi.org/10.1177/0271678X16630991
Lyck R, Ruderisch N, Moll AG et al (2009) Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo. J Cereb Blood Flow Metab 29(9):1491–1502. https://doi.org/10.1038/jcbfm.2009.72
Yusof SR, Avdeef A, Abbott NJ (2014) In vitro porcine blood-brain barrier model for permeability studies: pCEL-X software pKa(FLUX) method for aqueous boundary layer correction and detailed data analysis. Eur J Pharm Sci 65:98–111. https://doi.org/10.1016/j.ejps.2014.09.009
Patabendige A, Skinner RA, Abbott NJ (2013) Establishment of a simplified in vitro porcine blood-brain barrier model with high transendothelial electrical resistance. Brain Res 1521:1–15. https://doi.org/10.1016/j.brainres.2012.06.057
Culot M, Lundquist S, Vanuxeem D et al (2008) An in vitro blood-brain barrier model for high throughput (HTS) toxicological screening. Toxicol In Vitro 22(3):799–811. https://doi.org/10.1016/j.tiv.2007.12.016
Lippmann ES, Azarin SM, Kay JE et al (2012) Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol 30(8):783–791. https://doi.org/10.1038/nbt.2247
Murugan V (2009) Embryonic stem cell research: a decade of debate from Bush to Obama. Yale J Biol Med 82(3):101–103
Vazin T, Freed WJ (2010) Human embryonic stem cells: derivation, culture, and differentiation: a review. Restor Neurol Neurosci 28(4):589–603. https://doi.org/10.3233/RNN-2010-0543
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. https://doi.org/10.1016/j.cell.2006.07.024
Yagi M, Yamanaka S, Yamada Y (2017) Epigenetic foundations of pluripotent stem cells that recapitulate in vivo pluripotency. Lab Investig 97(10):1133–1141. https://doi.org/10.1038/labinvest.2017.87
Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920. https://doi.org/10.1126/science.1151526
Ebben JD, Zorniak M, Clark PA et al (2011) Introduction to induced pluripotent stem cells: advancing the potential for personalized medicine. World Neurosurg 76(3–4):270–275. https://doi.org/10.1016/j.wneu.2010.12.055
Inoue H, Nagata N, Kurokawa H et al (2014) iPS cells: a game changer for future medicine. EMBO J 33(5):409–417
Soldner F, Jaenisch R (2017) In vitro modeling of complex neurological diseases. In: Jaenisch R, Zhang F, Gage F (eds) Genome editing in neurosciences, Cham, pp 1–19. https://doi.org/10.1007/978-3-319-60192-2_1
Wong PC, Cai H, Borchelt DR et al (2002) Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 5(7):633–639. https://doi.org/10.1038/nn0702-633
Mehta D, Jackson R, Paul G et al (2017) Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs 26(6):735–739
Zhang SC, Wernig M, Duncan ID et al (2001) In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 19(12):1129–1133. https://doi.org/10.1038/nbt1201-1129
Marchetto MC, Carromeu C, Acab A et al (2010) A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143(4):527–539. https://doi.org/10.1016/j.cell.2010.10.016
Mattis VB, Svendsen CN (2011) Induced pluripotent stem cells: a new revolution for clinical neurology? Lancet Neurol 10(4):383–394
Tiscornia G, Vivas EL, Belmonte JCI (2011) Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med 17(12):1570–1576. https://doi.org/10.1038/nm.2504
Zhang Y, Xie X, Hu J et al (2020) Prospects of directly reprogrammed adult human neurons for neurodegenerative disease modeling and drug discovery: iN vs. iPSCs models. Front Neurosci 14:546484. https://doi.org/10.3389/fnins.2020.546484
Ebert AD, Yu J, Rose FF Jr et al (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457(7227):277–280. https://doi.org/10.1038/nature07677
Chang T, Zheng W, Tsark W et al (2011) Brief report: phenotypic rescue of induced pluripotent stem cell-derived motoneurons of a spinal muscular atrophy patient. Stem Cells 29(12):2090–2093. https://doi.org/10.1002/stem.749
Zhang X, Li Z, Liu Y et al (2021) Great expectations: induced pluripotent stem cell technologies in neurodevelopmental impairments. Int J Med Sci 18(2):459–473. https://doi.org/10.7150/ijms.51842
Cheffer A, Flitsch LJ, Krutenko T et al (2020) Human stem cell-based models for studying autism spectrum disorder-related neuronal dysfunction. Mol Autism 11(1):99. https://doi.org/10.1186/s13229-020-00383-w
Burnight ER, Bohrer LR, Giacalone JC et al (2018) CRISPR-Cas9-mediated correction of the 1.02 kb common deletion in CLN3 in induced pluripotent stem cells from patients with batten disease. CRISPR J 1:75–87. https://doi.org/10.1089/crispr.2017.0015
Lukovic D, Moreno-Manzano V, Rodriguez-Jimenez FJ et al (2017) hiPSC disease modeling of rare hereditary cerebellar ataxias: opportunities and future challenges. Neuroscientist 23(5):554–566. https://doi.org/10.1177/1073858416672652
Gough G, O'Brien NL, Alic I et al (2020) Modeling down syndrome in cells: from stem cells to organoids. Prog Brain Res 251:55–90. https://doi.org/10.1016/bs.pbr.2019.10.003
Tidball AM, Parent JM (2016) Concise review: exciting cells: Modeling genetic epilepsies with patient-derived induced pluripotent stem cells. Stem Cells 34(1):27–33. https://doi.org/10.1002/stem.2203
Abu Diab M, Eiges R (2019) The contribution of pluripotent stem cell (PSC)-based models to the study of Fragile X Syndrome (FXS). Brain Sci 9(2). https://doi.org/10.3390/brainsci9020042
Gomathi M, Balachandar V (2017) Novel therapeutic approaches: Rett syndrome and human induced pluripotent stem cell technology. Stem Cell Investig 4:20. https://doi.org/10.21037/sci.2017.02.11
Devineni A, Tohme S, Kody MT et al (2016) Stepping back to move forward: a current review of iPSCs in the fight against Alzheimer’s disease. Am J Stem Cells 5(3):99–106
Sances S, Bruijn LI, Chandran S et al (2016) Modeling ALS with motor neurons derived from human induced pluripotent stem cells. Nat Neurosci 19(4):542–553. https://doi.org/10.1038/nn.4273
Csobonyeiova M, Polak S, Danisovic L (2020) Recent overview of the use of iPSCs Huntington’s disease modeling and therapy. Int J Mol Sci 21(6). https://doi.org/10.3390/ijms21062239
Kouroupi G, Antoniou N, Prodromidou K et al (2020) Patient-derived induced pluripotent stem cell-based models in Parkinson’s disease for drug identification. Int J Mol Sci 21(19). https://doi.org/10.3390/ijms21197113
Weksler BB, Subileau EA, Perriere N et al (2005) Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19(13):1872–1874. https://doi.org/10.1096/fj.04-3458fje
Daneman R, Agalliu D, Zhou L et al (2009) Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci U S A 106(2):641–646. https://doi.org/10.1073/pnas.0805165106
Liebner S, Corada M, Bangsow T et al (2008) Wnt/beta-catenin signaling controls development of the blood-brain barrier. J Cell Biol 183(3):409–417. https://doi.org/10.1083/jcb.200806024
Crone C, Olesen SP (1982) Electrical resistance of brain microvascular endothelium. Brain Res 241(1):49–55. https://doi.org/10.1016/0006-8993(82)91227-6
Mizee MR, Wooldrik D, Lakeman KA et al (2013) Retinoic acid induces blood-brain barrier development. J Neurosci 33(4):1660–1671. https://doi.org/10.1523/JNEUROSCI.1338-12.2013
Lippmann ES, Al-Ahmad A, Azarin SM et al (2014) A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep 4:4160. https://doi.org/10.1038/srep04160
Stebbins MJ, Lippmann ES, Faubion MG et al (2018) Activation of RARalpha, RARgamma, or RXRalpha increases barrier tightness in human induced pluripotent stem cell-derived brain endothelial cells. Biotechnol J 13(2). https://doi.org/10.1002/biot.201700093
Katt ME, Xu ZS, Gerecht S et al (2016) Human brain microvascular endothelial cells derived from the BC1 iPS cell line exhibit a blood-brain barrier phenotype. PLoS One 11(4):e0152105. https://doi.org/10.1371/journal.pone.0152105
Cecchelli R, Aday S, Sevin E et al (2014) A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells. PLoS One 9(6):e99733. https://doi.org/10.1371/journal.pone.0099733
Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood-brain barrier. Acta Neurobiol Exp (Wars) 71(1):113–128
Qian T, Maguire SE, Canfield SG et al (2017) Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells. Sci Adv 3(11):e1701679. https://doi.org/10.1126/sciadv.1701679
Patel R, Alahmad AJ (2016) Growth-factor reduced Matrigel source influences stem cell derived brain microvascular endothelial cell barrier properties. Fluids Barriers CNS 13(6):6. https://doi.org/10.1186/s12987-016-0030-5
Neal EH, Marinelli NA, Shi Y et al (2019) A simplified, fully defined differentiation scheme for producing blood-brain barrier endothelial cells from human iPSCs. Stem Cell Rep 12(6):1380–1388. https://doi.org/10.1016/j.stemcr.2019.05.008
Canfield SG, Stebbins MJ, Morales BS et al (2017) An isogenic blood-brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. J Neurochem 140(6):874–888. https://doi.org/10.1111/jnc.13923
Patel R, Page S, Al-Ahmad AJ (2017) Isogenic blood-brain barrier models based on patient-derived stem cells display inter-individual differences in cell maturation and functionality. J Neurochem 142(1):74–88. https://doi.org/10.1111/jnc.14040
Stebbins MJ, Gastfriend BD, Canfield SG et al (2019) Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties. Sci Adv 5(3):eaau7375. https://doi.org/10.1126/sciadv.aau7375
Mantle JL, Min L, Lee KH (2016) 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 13(12):4191–4198. https://doi.org/10.1021/acs.molpharmaceut.6b00818
Wilson HK, Canfield SG, Shusta EV et al (2014) Concise review: tissue-specific microvascular endothelial cells derived from human pluripotent stem cells. Stem Cells 32(12):3037–3045. https://doi.org/10.1002/stem.1797
DeStefano JG, Xu ZS, Williams AJ et al (2017) Effect of shear stress on iPSC-derived human brain microvascular endothelial cells (dhBMECs). Fluids Barriers CNS 14(1):20. https://doi.org/10.1186/s12987-017-0068-z
Lim RG, Quan C, Reyes-Ortiz AM et al (2017) Huntington’s disease iPSC-derived brain microvascular endothelial cells reveal WNT-mediated Angiogenic and blood-brain barrier deficits. Cell Rep 19(7):1365–1377. https://doi.org/10.1016/j.celrep.2017.04.021
Vatine GD, Al-Ahmad A, Barriga BK et al (2017) Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood-brain barrier. Cell Stem Cell 20(6):831–843.e835. https://doi.org/10.1016/j.stem.2017.04.002
Katt ME, Mayo LN, Ellis SE et al (2019) The role of mutations associated with familial neurodegenerative disorders on blood-brain barrier function in an iPSC model. Fluids Barriers CNS 16(1):20. https://doi.org/10.1186/s12987-019-0139-4
Raut S, Patel R, Al-Ahmad AJ (2021) Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro. Fluids Barriers CNS 18(1):3. https://doi.org/10.1186/s12987-020-00235-y
Berndt P, Winkler L, Cording J et al (2019) Tight junction proteins at the blood-brain barrier: far more than claudin-5. Cell Mol Life Sci 76(10):1987–2002. https://doi.org/10.1007/s00018-019-03030-7
Al-Ahmad AJ (2017) 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 313(4):C421–C429. https://doi.org/10.1152/ajpcell.00116.2017
Albekairi TH, Vaidya B, Patel R et al (2019) Brain delivery of a potent opioid receptor agonist, Biphalin during ischemic stroke: role of Organic Anion Transporting Polypeptide (OATP). Pharmaceutics 11(9). https://doi.org/10.3390/pharmaceutics11090467
Nakagawa S, Deli MA, Kawaguchi H et al (2009) A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int 54(3–4):253–263. https://doi.org/10.1016/j.neuint.2008.12.002
Al Ahmad A, Gassmann M, Ogunshola OO (2009) Maintaining blood-brain barrier integrity: pericytes perform better than astrocytes during prolonged oxygen deprivation. J Cell Physiol 218(3):612–622. https://doi.org/10.1002/jcp.21638
Weidenfeller C, Svendsen CN, Shusta EV (2007) Differentiating embryonic neural progenitor cells induce blood-brain barrier properties. J Neurochem 101(2):555–565. https://doi.org/10.1111/j.1471-4159.2006.04394.x
Demeuse P, Kerkhofs A, Struys-Ponsar C et al (2002) Compartmentalized coculture of rat brain endothelial cells and astrocytes: a syngenic model to study the blood-brain barrier. J Neurosci Methods 121(1):21–31. https://doi.org/10.1016/s0165-0270(02)00225-x
Cucullo L, McAllister MS, Kight K et al (2002) A new dynamic in vitro model for the multidimensional study of astrocyte-endothelial cell interactions at the blood-brain barrier. Brain Res 951(2):243–254. https://doi.org/10.1016/s0006-8993(02)03167-0
Dehouck MP, Meresse S, Delorme P et al (1990) An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J Neurochem 54(5):1798–1801. https://doi.org/10.1111/j.1471-4159.1990.tb01236.x
Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325(6101):253–257. https://doi.org/10.1038/325253a0
Arthur FE, Shivers RR, Bowman PD (1987) Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model. Brain Res 433(1):155–159. https://doi.org/10.1016/0165-3806(87)90075-7
Rhea EM, Logsdon AF, Hansen KM et al (2020) The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Nat Neurosci. https://doi.org/10.1038/s41593-020-00771-8
Buzhdygan TP, DeOre BJ, Baldwin-Leclair A et al (2020) The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol Dis 146:105131. https://doi.org/10.1016/j.nbd.2020.105131
Alimonti JB, Ribecco-Lutkiewicz M, Sodja C et al (2018) Zika virus crosses an in vitro human blood brain barrier model. Fluids Barriers CNS 15(1):15. https://doi.org/10.1186/s12987-018-0100-y
Kim BJ, Shusta EV, Doran KS (2019) Past and current perspectives in modeling bacteria and blood-brain barrier interactions. Front Microbiol 10:1336. https://doi.org/10.3389/fmicb.2019.01336
Kim BJ, Bee OB, McDonagh MA et al (2017) Modeling group B streptococcus and blood-brain barrier interaction by using induced pluripotent stem cell-derived brain endothelial cells. mSphere 2(6). https://doi.org/10.1128/mSphere.00398-17
Patel R, Hossain MA, German N et al (2018) Gliotoxin penetrates and impairs the integrity of the human blood-brain barrier in vitro. Mycotoxin Res 34(4):257–268. https://doi.org/10.1007/s12550-018-0320-7
Nishihara H, Gastfriend BD, Soldati S et al (2020) Advancing human induced pluripotent stem cell-derived blood-brain barrier models for studying immune cell interactions. FASEB J 34(12):16693–16715. https://doi.org/10.1096/fj.202001507RR
Martinez A, Al-Ahmad AJ (2019) Effects of glyphosate and aminomethylphosphonic acid on an isogeneic model of the human blood-brain barrier. Toxicol Lett 304:39–49. https://doi.org/10.1016/j.toxlet.2018.12.013
Park TE, Mustafaoglu N, Herland A et al (2019) Hypoxia-enhanced blood-brain barrier chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat Commun 10(1):2621. https://doi.org/10.1038/s41467-019-10588-0
Haley MJ, Lawrence CB (2017) The blood-brain barrier after stroke: structural studies and the role of transcytotic vesicles. J Cereb Blood Flow Metab 37(2):456–470. https://doi.org/10.1177/0271678X16629976
Zhang Z, Yan J, Shi H (2016) Role of hypoxia inducible factor 1 in Hyperglycemia-exacerbated blood-brain barrier disruption in ischemic stroke. Neurobiol Dis 95:82–92. https://doi.org/10.1016/j.nbd.2016.07.012
Yan J, Zhou B, Taheri S et al (2011) Differential effects of HIF-1 inhibition by YC-1 on the overall outcome and blood-brain barrier damage in a rat model of ischemic stroke. PLoS One 6(11):e27798. https://doi.org/10.1371/journal.pone.0027798
Yan J, Zhang Z, Shi H (2012) HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cell Mol Life Sci 69(1):115–128. https://doi.org/10.1007/s00018-011-0731-5
Ogunshola OO, Al-Ahmad A (2012) HIF-1 at the blood-brain barrier: a mediator of permeability? High Alt Med Biol 13(3):153–161. https://doi.org/10.1089/ham.2012.1052
Engelhardt S, Patkar S, Ogunshola OO (2014) Cell-specific blood-brain barrier regulation in health and disease: a focus on hypoxia. Br J Pharmacol 171(5):1210–1230. https://doi.org/10.1111/bph.12489
Engelhardt S, Al-Ahmad AJ, Gassmann M et al (2014) Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism. J Cell Physiol 229(8):1096–1105. https://doi.org/10.1002/jcp.24544
Deli MA, Abraham CS, Kataoka Y et al (2005) Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol 25(1):59–127. https://doi.org/10.1007/s10571-004-1377-8
Page S, Raut S, Al-Ahmad A (2019) Oxygen-glucose deprivation/Reoxygenation-induced barrier disruption at the human blood-brain barrier is partially mediated through the HIF-1 pathway. NeuroMolecular Med 21(4):414–431. https://doi.org/10.1007/s12017-019-08531-z
Page S, Munsell A, Al-Ahmad AJ (2016) Cerebral hypoxia/ischemia selectively disrupts tight junctions complexes in stem cell-derived human brain microvascular endothelial cells. Fluids Barriers CNS 13(1):16. https://doi.org/10.1186/s12987-016-0042-1
Natah SS, Srinivasan S, Pittman Q et al (2009) Effects of acute hypoxia and hyperthermia on the permeability of the blood-brain barrier in adult rats. J Appl Physiol (1985) 107(4):1348–1356. https://doi.org/10.1152/japplphysiol.91484.2008
Witt KA, Mark KS, Sandoval KE et al (2008) Reoxygenation stress on blood-brain barrier paracellular permeability and edema in the rat. Microvasc Res 75(1):91–96. https://doi.org/10.1016/j.mvr.2007.06.004
Yeh WL, Lu DY, Lin CJ et al (2007) Inhibition of hypoxia-induced increase of blood-brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression. Mol Pharmacol 72(2):440–449. https://doi.org/10.1124/mol.107.036418
Koto T, Takubo K, Ishida S et al (2007) Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells. Am J Pathol 170(4):1389–1397. https://doi.org/10.2353/ajpath.2007.060693
Kaur C, Sivakumar V, Zhang Y et al (2006) Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia 54(8):826–839. https://doi.org/10.1002/glia.20420
Hayashi K, Nakao S, Nakaoke R et al (2004) Effects of hypoxia on endothelial/pericytic co-culture model of the blood-brain barrier. Regul Pept 123(1–3):77–83. https://doi.org/10.1016/j.regpep.2004.05.023
Fischer S, Wiesnet M, Marti HH et al (2004) Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells. J Cell Physiol 198(3):359–369. https://doi.org/10.1002/jcp.10417
Witt KA, Mark KS, Hom S et al (2003) Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol 285(6):H2820–H2831. https://doi.org/10.1152/ajpheart.00589.2003
Schoch HJ, Fischer S, Marti HH (2002) Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 125(Pt 11):2549–2557. https://doi.org/10.1093/brain/awf257
Fischer S, Wobben M, Marti HH et al (2002) Hypoxia-induced hyperpermeability in brain microvessel endothelial cells involves VEGF-mediated changes in the expression of zonula occludens-1. Microvasc Res 63(1):70–80. https://doi.org/10.1006/mvre.2001.2367
Plateel M, Dehouck MP, Torpier G et al (1995) Hypoxia increases the susceptibility to oxidant stress and the permeability of the blood-brain barrier endothelial cell monolayer. J Neurochem 65(5):2138–2145. https://doi.org/10.1046/j.1471-4159.1995.65052138.x
Lee CAA, Seo HS, Armien AG et al (2018) Modeling and rescue of defective blood-brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients. Fluids Barriers CNS 15(1):9. https://doi.org/10.1186/s12987-018-0094-5
Kinarivala N, Morsy A, Patel R et al (2020) An iPSC-derived neuron model of CLN3 disease facilitates small molecule phenotypic screening. ACS Pharmacol Transl Sci 3(5):931–947. https://doi.org/10.1021/acsptsci.0c00077
Clark PA, Al-Ahmad AJ, Qian T et al (2016) Analysis of cancer-targeting Alkylphosphocholine analogue permeability characteristics using a human induced pluripotent stem cell blood-brain barrier model. Mol Pharm 13(9):3341–3349. https://doi.org/10.1021/acs.molpharmaceut.6b00441
Lippmann ES, Azarin SM, Palecek SP et al (2020) Commentary on human pluripotent stem cell-based blood-brain barrier models. Fluids Barriers CNS 17(1):64. https://doi.org/10.1186/s12987-020-00222-3
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Pervaiz, I., Al-Ahmad, A.J. (2022). In Vitro Models of the Human Blood–Brain Barrier Utilising Human Induced Pluripotent Stem Cells: Opportunities and Challenges. In: Stone, N. (eds) The Blood-Brain Barrier. Methods in Molecular Biology, vol 2492. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2289-6_3
Download citation
DOI: https://doi.org/10.1007/978-1-0716-2289-6_3
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-2288-9
Online ISBN: 978-1-0716-2289-6
eBook Packages: Springer Protocols