{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T02:02:26Z","timestamp":1792116146402,"version":"4.4.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["1R21NS127215-01"],"award-info":[{"award-number":["1R21NS127215-01"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Fluids Barriers CNS"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Blood\u2013brain barrier (BBB) disruption is a central feature of cerebral malaria (CM), a severe complication of\u00a0<jats:italic>Plasmodium falciparum<\/jats:italic>\u00a0(<jats:italic>Pf<\/jats:italic>) infections. In CM, sequestration of <jats:italic>Pf<\/jats:italic>-infected red blood cells (<jats:italic>Pf<\/jats:italic>-iRBCs) to brain endothelial cells combined with inflammation, hemolysis, microvasculature obstruction and endothelial dysfunction mediates BBB disruption, resulting in severe neurologic symptoms including coma and seizures, potentially leading to death or long-term sequelae. In vitro models have advanced our knowledge of CM-mediated BBB disruption, but their physiological relevance remains uncertain. Using human induced pluripotent stem cell-derived brain microvascular endothelial cells (hiPSC-BMECs), we aimed to develop a novel in vitro model of the BBB in CM, exhibiting enhanced barrier properties.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>hiPSC-BMECs were co-cultured with HB3var03 strain <jats:italic>Pf-<\/jats:italic>iRBCs up to 9\u00a0h. Barrier integrity was measured using transendothelial electrical resistance (TEER) and sodium fluorescein permeability assays. Localization and expression of tight junction (TJ) proteins (occludin, zonula occludens-1, claudin-5), cellular adhesion molecules (ICAM-1, VCAM-1), and endothelial surface markers (EPCR) were determined using immunofluorescence imaging (IF) and western blotting (WB). Expression of angiogenic and cell stress markers were measured using multiplex proteome profiler arrays.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>After 6-h of co-culture with <jats:italic>Pf-<\/jats:italic>iRBCs, hiPSC-BMECs showed reduced TEER and increased sodium fluorescein permeability compared to co-culture with uninfected RBCs, indicative of a leaky barrier. We observed disruptions in localization of occludin, zonula occludens-1, and claudin-5 by IF, but no change in protein expression by WB in <jats:italic>Pf-<\/jats:italic>iRBC co-cultures. Expression of ICAM-1 and VCAM-1 but not EPCR was elevated in hiPSC-BMECs with <jats:italic>Pf-<\/jats:italic>iRBC co-culture compared to uninfected RBC co-culture. In addition, there was an increase in expression of angiogenin, platelet factor-4, and phospho-heat shock protein-27 in the <jats:italic>Pf-<\/jats:italic>iRBCs co-culture compared to uninfected RBC co-culture.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>These findings demonstrate the validity of our hiPSC-BMECs based model of the BBB, that displays enhanced barrier integrity and appropriate TJ protein localization. In the hiPSC-BMEC co-culture with <jats:italic>Pf<\/jats:italic>-iRBCs, reduced TEER, increased paracellular permeability, changes in TJ protein localization, increase in expression of adhesion molecules, and markers of angiogenesis and cellular stress all point towards a novel model with enhanced barrier properties, suitable for investigating pathogenic mechanisms underlying BBB disruption in CM.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12987-024-00541-9","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T15:09:55Z","timestamp":1714576195000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A human pluripotent stem cell-derived in vitro\u00a0model of the blood\u2013brain barrier in cerebral malaria"],"prefix":"10.1186","volume":"21","author":[{"given":"Adnan","family":"Gopinadhan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Conroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandy C.","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott G.","family":"Canfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dibyadyuti","family":"Datta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,1]]},"reference":[{"issue":"4","key":"541_CR1","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1046\/j.1365-2990.1999.00188.x","volume":"25","author":"H Brown","year":"1999","unstructured":"Brown H, et al. Evidence of blood\u2013brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol. 1999;25(4):331\u201340.","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"3","key":"541_CR2","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1136\/adc.76.3.219","volume":"76","author":"CR Newton","year":"1997","unstructured":"Newton CR, et al. Intracranial hypertension in Africans with cerebral malaria. Arch Dis Child. 1997;76(3):219\u201326.","journal-title":"Arch Dis Child"},{"issue":"2","key":"541_CR3","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/nm986","volume":"10","author":"TE Taylor","year":"2004","unstructured":"Taylor TE, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med. 2004;10(2):143\u20135.","journal-title":"Nat Med"},{"issue":"1","key":"541_CR4","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s12916-019-1291-z","volume":"17","author":"AL Conroy","year":"2019","unstructured":"Conroy AL, Datta D, John CC. What causes severe malaria and its complications in children? Lessons learned over the past 15 years. BMC Med. 2019;17(1):52.","journal-title":"BMC Med"},{"issue":"7","key":"541_CR5","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.pt.2019.04.010","volume":"35","author":"G Nishanth","year":"2019","unstructured":"Nishanth G, Schluter D. Blood\u2013brain barrier in cerebral malaria: pathogenesis and therapeutic intervention. Trends Parasitol. 2019;35(7):516\u201328.","journal-title":"Trends Parasitol"},{"issue":"3","key":"541_CR6","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1172\/JCI133474","volume":"130","author":"BA Riggle","year":"2020","unstructured":"Riggle BA, et al. CD8+ T cells target cerebrovasculature in children with cerebral malaria. J Clin Invest. 2020;130(3):1128\u201338.","journal-title":"J Clin Invest"},{"issue":"6","key":"541_CR7","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1093\/cid\/ciz325","volume":"70","author":"D Datta","year":"2020","unstructured":"Datta D, et al. Elevated cerebrospinal fluid tau protein concentrations on admission are associated with long-term neurologic and cognitive impairment in ugandan children with cerebral malaria. Clin Infect Dis. 2020;70(6):1161\u20138.","journal-title":"Clin Infect Dis"},{"issue":"12","key":"541_CR8","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.38515","volume":"4","author":"D Datta","year":"2021","unstructured":"Datta D, et al. Association of plasma tau with mortality and long-term neurocognitive impairment in survivors of pediatric cerebral malaria and severe malarial anemia. JAMA Netw Open. 2021;4(12): e2138515.","journal-title":"JAMA Netw Open"},{"issue":"4","key":"541_CR9","doi-asserted-by":"publisher","first-page":"345","DOI":"10.4269\/ajtmh.2003.69.345","volume":"69","author":"E Pongponratn","year":"2003","unstructured":"Pongponratn E, et al. An ultrastructural study of the brain in fatal Plasmodium falciparum malaria. Am J Trop Med Hyg. 2003;69(4):345\u201359.","journal-title":"Am J Trop Med Hyg"},{"issue":"5","key":"541_CR10","doi-asserted-by":"publisher","first-page":"642","DOI":"10.4269\/ajtmh.1994.51.642","volume":"51","author":"JK Patnaik","year":"1994","unstructured":"Patnaik JK, et al. Vascular clogging, mononuclear cell margination, and enhanced vascular permeability in the pathogenesis of human cerebral malaria. Am J Trop Med Hyg. 1994;51(5):642\u20137.","journal-title":"Am J Trop Med Hyg"},{"key":"541_CR11","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3389\/fcimb.2015.00075","volume":"5","author":"PK Sahu","year":"2015","unstructured":"Sahu PK, et al. Pathogenesis of cerebral malaria: new diagnostic tools, biomarkers, and therapeutic approaches. Front Cell Infect Microbiol. 2015;5:75.","journal-title":"Front Cell Infect Microbiol"},{"key":"541_CR12","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00193-17","author":"S Mohanty","year":"2017","unstructured":"Mohanty S, et al. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain. mSphere. 2017. https:\/\/doi.org\/10.1128\/mSphere.00193-17.","journal-title":"mSphere"},{"issue":"9","key":"541_CR13","doi-asserted-by":"publisher","first-page":"e734","DOI":"10.1097\/CCM.0000000000004469","volume":"48","author":"BJ Ouma","year":"2020","unstructured":"Ouma BJ, et al. Endothelial activation, acute kidney injury, and cognitive impairment in pediatric severe malaria. Crit Care Med. 2020;48(9):e734\u201343.","journal-title":"Crit Care Med"},{"issue":"12","key":"541_CR14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084181","volume":"8","author":"S Adukpo","year":"2013","unstructured":"Adukpo S, et al. High plasma levels of soluble intercellular adhesion molecule (ICAM)-1 are associated with cerebral malaria. PLoS ONE. 2013;8(12): e84181.","journal-title":"PLoS ONE"},{"issue":"3","key":"541_CR15","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.bbrc.2005.07.151","volume":"335","author":"L Treeratanapiboon","year":"2005","unstructured":"Treeratanapiboon L, et al. In vitro study of malaria parasite induced disruption of blood\u2013brain barrier. Biochem Biophys Res Commun. 2005;335(3):810\u20138.","journal-title":"Biochem Biophys Res Commun"},{"issue":"3","key":"541_CR16","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1007\/s00436-023-07782-x","volume":"122","author":"TF Pais","year":"2023","unstructured":"Pais TF, Penha-Goncalves C. In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors. Parasitol Res. 2023;122(3):729\u201337.","journal-title":"Parasitol Res"},{"issue":"3","key":"541_CR17","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1128\/IAI.01233-13","volume":"82","author":"Y Adams","year":"2014","unstructured":"Adams Y, et al. Rosetting Plasmodium falciparum-infected erythrocytes bind to human brain microvascular endothelial cells in vitro, demonstrating a dual adhesion phenotype mediated by distinct P. falciparum erythrocyte membrane protein 1 domains. Infect Immun. 2014;82(3):949\u201359.","journal-title":"Infect Immun"},{"key":"541_CR18","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201266","author":"Y Adams","year":"2021","unstructured":"Adams Y, et al. Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood\u2013brain barrier in cerebral malaria. J Exp Med. 2021. https:\/\/doi.org\/10.1084\/jem.20201266.","journal-title":"J Exp Med"},{"issue":"7","key":"541_CR19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001021","volume":"6","author":"R Jambou","year":"2010","unstructured":"Jambou R, et al. Plasmodium falciparum adhesion on human brain microvascular endothelial cells involves transmigration-like cup formation and induces opening of intercellular junctions. PLoS Pathog. 2010;6(7): e1001021.","journal-title":"PLoS Pathog"},{"issue":"5","key":"541_CR20","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1177\/0271678X16630991","volume":"36","author":"HC Helms","year":"2016","unstructured":"Helms HC, et al. In vitro models of the blood\u2013brain 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\u201390.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"6","key":"541_CR21","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1083\/jcb.115.6.1725","volume":"115","author":"LL Rubin","year":"1991","unstructured":"Rubin LL, et al. A cell culture model of the blood\u2013brain barrier. J Cell Biol. 1991;115(6):1725\u201335.","journal-title":"J Cell Biol"},{"issue":"7","key":"541_CR22","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1002\/jnr.23964","volume":"95","author":"E Biemans","year":"2017","unstructured":"Biemans E, et al. Limitations of the hCMEC\/D3 cell line as a model for Abeta clearance by the human blood\u2013brain barrier. J Neurosci Res. 2017;95(7):1513\u201322.","journal-title":"J Neurosci Res"},{"issue":"1","key":"541_CR23","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/2045-8118-10-33","volume":"10","author":"DE Eigenmann","year":"2013","unstructured":"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\u2013brain barrier model for drug permeability studies. Fluids Barriers CNS. 2013;10(1):33.","journal-title":"Fluids Barriers CNS"},{"issue":"8","key":"541_CR24","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1161\/STROKEAHA.114.005427","volume":"45","author":"Y He","year":"2014","unstructured":"He Y, et al. Cell-culture models of the blood\u2013brain barrier. Stroke. 2014;45(8):2514\u201326.","journal-title":"Stroke"},{"issue":"6","key":"541_CR25","doi-asserted-by":"publisher","first-page":"3262","DOI":"10.1128\/IAI.01625-05","volume":"74","author":"AK Tripathi","year":"2006","unstructured":"Tripathi AK, Sullivan DJ, Stins MF. Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB. Infect Immun. 2006;74(6):3262\u201370.","journal-title":"Infect Immun"},{"issue":"7","key":"541_CR26","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1086\/512083","volume":"195","author":"AK Tripathi","year":"2007","unstructured":"Tripathi AK, Sullivan DJ, Stins MF. Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood\u2013brain barrier endothelial cell monolayers. J Infect Dis. 2007;195(7):942\u201350.","journal-title":"J Infect Dis"},{"key":"541_CR27","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00420-19","author":"M Bernabeu","year":"2019","unstructured":"Bernabeu M, et al. Binding heterogeneity of Plasmodium falciparum to engineered 3D brain microvessels is mediated by EPCR and ICAM-1. MBio. 2019. https:\/\/doi.org\/10.1128\/mBio.00420-19.","journal-title":"MBio"},{"key":"541_CR28","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00615-16","author":"M Avril","year":"2016","unstructured":"Avril M, et al. Interaction between endothelial protein C receptor and intercellular adhesion molecule 1 to mediate binding of Plasmodium falciparum-infected erythrocytes to endothelial cells. MBio. 2016. https:\/\/doi.org\/10.1128\/mBio.00615-16.","journal-title":"MBio"},{"issue":"13","key":"541_CR29","doi-asserted-by":"publisher","first-page":"2851","DOI":"10.1182\/bloodadvances.2019001258","volume":"4","author":"CA Moxon","year":"2020","unstructured":"Moxon CA, et al. Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria. Blood Adv. 2020;4(13):2851\u201364.","journal-title":"Blood Adv"},{"issue":"1","key":"541_CR30","doi-asserted-by":"publisher","first-page":"13142","DOI":"10.1038\/s41598-019-49530-1","volume":"9","author":"M Avril","year":"2019","unstructured":"Avril M, et al. Interplay of Plasmodium falciparum and thrombin in brain endothelial barrier disruption. Sci Rep. 2019;9(1):13142.","journal-title":"Sci Rep"},{"issue":"Pt 11","key":"541_CR31","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1099\/jmm.0.05230-0","volume":"52","author":"SHM Chen","year":"2003","unstructured":"Chen SHM, et al. Cryptococcus neoformans induces alterations in the cytoskeleton of human brain microvascular endothelial cells. J Med Microbiol. 2003;52(Pt 11):961\u201370.","journal-title":"J Med Microbiol"},{"issue":"9","key":"541_CR32","doi-asserted-by":"publisher","first-page":"4985","DOI":"10.1128\/IAI.72.9.4985-4995.2004","volume":"72","author":"YC Chang","year":"2004","unstructured":"Chang YC, et al. Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood\u2013brain barrier. Infect Immun. 2004;72(9):4985\u201395.","journal-title":"Infect Immun"},{"issue":"1","key":"541_CR33","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/sj.jcbfm.9600518","volume":"28","author":"AR Calabria","year":"2008","unstructured":"Calabria AR, Shusta EV. A genomic comparison of in vivo and in vitro brain microvascular endothelial cells. J Cereb Blood Flow Metab. 2008;28(1):135\u201348.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"7","key":"541_CR34","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1038\/nprot.2010.76","volume":"5","author":"MJ Bernas","year":"2010","unstructured":"Bernas MJ, et al. Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood\u2013brain barrier. Nat Protoc. 2010;5(7):1265\u201372.","journal-title":"Nat Protoc"},{"issue":"4","key":"541_CR35","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1007\/s12550-018-0320-7","volume":"34","author":"R Patel","year":"2018","unstructured":"Patel R, et al. Gliotoxin penetrates and impairs the integrity of the human blood\u2013brain barrier in vitro. Mycotoxin Res. 2018;34(4):257\u201368.","journal-title":"Mycotoxin Res"},{"issue":"3","key":"541_CR36","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.stemcr.2019.01.005","volume":"12","author":"T Faal","year":"2019","unstructured":"Faal T, et al. Induction of mesoderm and neural crest-derived pericytes from human pluripotent stem cells to study blood\u2013brain barrier interactions. Stem Cell Rep. 2019;12(3):451\u201360.","journal-title":"Stem Cell Rep"},{"issue":"6","key":"541_CR37","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1111\/jnc.13923","volume":"140","author":"SG Canfield","year":"2017","unstructured":"Canfield SG, et al. An isogenic blood\u2013brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. J Neurochem. 2017;140(6):874\u201388.","journal-title":"J Neurochem"},{"key":"541_CR38","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.ymeth.2015.10.016","volume":"101","author":"MJ Stebbins","year":"2016","unstructured":"Stebbins MJ, et al. Differentiation and characterization of human pluripotent stem cell-derived brain microvascular endothelial cells. Methods. 2016;101:93\u2013102.","journal-title":"Methods"},{"key":"541_CR39","doi-asserted-by":"publisher","first-page":"4160","DOI":"10.1038\/srep04160","volume":"4","author":"ES Lippmann","year":"2014","unstructured":"Lippmann ES, et al. A retinoic acid-enhanced, multicellular human blood\u2013brain barrier model derived from stem cell sources. Sci Rep. 2014;4:4160.","journal-title":"Sci Rep"},{"issue":"6","key":"541_CR40","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1016\/j.stemcr.2019.05.008","volume":"12","author":"EH Neal","year":"2019","unstructured":"Neal EH, et al. A Simplified, fully defined differentiation scheme for producing blood\u2013brain barrier endothelial cells from human iPSCs. Stem Cell Reps. 2019;12(6):1380\u20138.","journal-title":"Stem Cell Reps"},{"issue":"8","key":"541_CR41","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/nbt.2247","volume":"30","author":"ES Lippmann","year":"2012","unstructured":"Lippmann ES, et al. Derivation of blood\u2013brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol. 2012;30(8):783\u201391.","journal-title":"Nat Biotechnol"},{"issue":"1","key":"541_CR42","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1111\/jnc.14040","volume":"142","author":"R Patel","year":"2017","unstructured":"Patel R, Page S, Al-Ahmad AJ. Isogenic blood\u2013brain barrier models based on patient-derived stem cells display inter-individual differences in cell maturation and functionality. J Neurochem. 2017;142(1):74\u201388.","journal-title":"J Neurochem"},{"key":"541_CR43","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.835649","volume":"16","author":"JM Hughes","year":"2022","unstructured":"Hughes JM, et al. The effects of propofol on a human in vitro blood\u2013brain barrier model. Front Cell Neurosci. 2022;16: 835649.","journal-title":"Front Cell Neurosci"},{"issue":"1","key":"541_CR44","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/2045-8118-10-16","volume":"10","author":"B Weksler","year":"2013","unstructured":"Weksler B, Romero IA, Couraud PO. The hCMEC\/D3 cell line as a model of the human blood\u2013brain barrier. Fluids Barriers CNS. 2013;10(1):16.","journal-title":"Fluids Barriers CNS"},{"key":"541_CR45","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.12688\/f1000research.7142.1","volume":"4","author":"P Sreekanthreddy","year":"2015","unstructured":"Sreekanthreddy P, et al. A three-dimensional model of the human blood\u2013brain barrier to analyse the transport of nanoparticles and astrocyte\/endothelial interactions. F1000Res. 2015;4:1279.","journal-title":"F1000Res"},{"issue":"2\u20133","key":"541_CR46","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/S0169-409X(98)00083-0","volume":"36","author":"R Cecchelli","year":"1999","unstructured":"Cecchelli R, et al. In vitro model for evaluating drug transport across the blood\u2013brain barrier. Adv Drug Deliv Rev. 1999;36(2\u20133):165\u201378.","journal-title":"Adv Drug Deliv Rev"},{"issue":"8","key":"541_CR47","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/S1471-4922(02)02353-X","volume":"18","author":"S Adams","year":"2002","unstructured":"Adams S, Brown H, Turner G. Breaking down the blood\u2013brain barrier: signaling a path to cerebral malaria? Trends Parasitol. 2002;18(8):360\u20136.","journal-title":"Trends Parasitol"},{"issue":"1","key":"541_CR48","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1186\/s12936-020-03447-7","volume":"19","author":"NK Mita-Mendoza","year":"2020","unstructured":"Mita-Mendoza NK, et al. Dimethyl fumarate reduces TNF and Plasmodium falciparum induced brain endothelium activation in vitro. Malar J. 2020;19(1):376.","journal-title":"Malar J"},{"issue":"26","key":"541_CR49","doi-asserted-by":"publisher","first-page":"E1772","DOI":"10.1073\/pnas.1120461109","volume":"109","author":"A Claessens","year":"2012","unstructured":"Claessens A, et al. A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. Proc Natl Acad Sci U S A. 2012;109(26):E1772\u201381.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"541_CR50","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.711784","volume":"13","author":"A Kapoor","year":"2021","unstructured":"Kapoor A, et al. Increased levels of circulating angiogenic cells and signaling proteins in older adults with cerebral small vessel disease. Front Aging Neurosci. 2021;13: 711784.","journal-title":"Front Aging Neurosci"},{"key":"541_CR51","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.pneurobio.2017.10.001","volume":"163\u2013164","author":"X Jiang","year":"2018","unstructured":"Jiang X, et al. Blood\u2013brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol. 2018;163\u2013164:144\u201371.","journal-title":"Prog Neurobiol"},{"issue":"5","key":"541_CR52","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1111\/j.1524-475X.2012.00819.x","volume":"20","author":"SC Pan","year":"2012","unstructured":"Pan SC, et al. Angiogenin expression in burn blister fluid: implications for its role in burn wound neovascularization. Wound Repair Regen. 2012;20(5):731\u20139.","journal-title":"Wound Repair Regen"},{"issue":"2","key":"541_CR53","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.bbrc.2006.11.047","volume":"352","author":"HM Kim","year":"2007","unstructured":"Kim HM, et al. Angiogenin-induced protein kinase B\/Akt activation is necessary for angiogenesis but is independent of nuclear translocation of angiogenin in HUVE cells. Biochem Biophys Res Commun. 2007;352(2):509\u201313.","journal-title":"Biochem Biophys Res Commun"},{"issue":"1","key":"541_CR54","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1006\/bbrc.2001.5568","volume":"287","author":"S Liu","year":"2001","unstructured":"Liu S, et al. Angiogenin activates Erk1\/2 in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2001;287(1):305\u201310.","journal-title":"Biochem Biophys Res Commun"},{"key":"541_CR55","first-page":"1","volume-title":"Encyclopedia of inflammatory diseases","author":"CA Gleissner","year":"2015","unstructured":"Gleissner CA. CXCL4 und CXCL4L1. In: Parnham M, editor. Encyclopedia of inflammatory diseases. Basel: Springer Basel; 2015. p. 1\u20137."},{"issue":"6","key":"541_CR56","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1080\/17474086.2016.1179571","volume":"9","author":"SC Wassmer","year":"2016","unstructured":"Wassmer SC, Grau GE. Platelets as pathogenetic effectors and killer cells in cerebral malaria. Expert Rev Hematol. 2016;9(6):515\u20137.","journal-title":"Expert Rev Hematol"},{"issue":"6112","key":"541_CR57","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1126\/science.1228892","volume":"338","author":"BJ McMorran","year":"2012","unstructured":"McMorran BJ, et al. Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science. 2012;338(6112):1348\u201351.","journal-title":"Science"},{"issue":"2","key":"541_CR58","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.chom.2008.07.003","volume":"4","author":"K Srivastava","year":"2008","unstructured":"Srivastava K, et al. Platelet factor 4 mediates inflammation in experimental cerebral malaria. Cell Host Microbe. 2008;4(2):179\u201387.","journal-title":"Cell Host Microbe"},{"issue":"1","key":"541_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111930","volume":"42","author":"AL Gray","year":"2023","unstructured":"Gray AL, et al. Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors. Cell Rep. 2023;42(1): 111930.","journal-title":"Cell Rep"},{"issue":"3","key":"541_CR60","doi-asserted-by":"publisher","first-page":"325","DOI":"10.2174\/1871527311312030006","volume":"12","author":"RK Leak","year":"2013","unstructured":"Leak RK, et al. HSP27 protects the blood\u2013brain barrier against ischemia-induced loss of integrity. CNS Neurol Disord Drug Targets. 2013;12(3):325\u201337.","journal-title":"CNS Neurol Disord Drug Targets"},{"issue":"7","key":"541_CR61","doi-asserted-by":"publisher","first-page":"E1243","DOI":"10.1073\/pnas.1621174114","volume":"114","author":"Y Shi","year":"2017","unstructured":"Shi Y, et al. Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood\u2013brain barrier disruption after ischemic brain injury. Proc Natl Acad Sci U S A. 2017;114(7):E1243\u201352.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"541_CR62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0198039","volume":"13","author":"Y Shimada","year":"2018","unstructured":"Shimada Y, et al. Phosphorylated recombinant HSP27 protects the brain and attenuates blood\u2013brain barrier disruption following stroke in mice receiving intravenous tissue-plasminogen activator. PLoS ONE. 2018;13(5): e0198039.","journal-title":"PLoS ONE"}],"container-title":["Fluids and Barriers of the CNS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12987-024-00541-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12987-024-00541-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12987-024-00541-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T16:02:13Z","timestamp":1714579333000},"score":1,"resource":{"primary":{"URL":"https:\/\/fluidsbarrierscns.biomedcentral.com\/articles\/10.1186\/s12987-024-00541-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,1]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["541"],"URL":"https:\/\/doi.org\/10.1186\/s12987-024-00541-9","relation":{},"ISSN":["2045-8118"],"issn-type":[{"value":"2045-8118","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,1]]},"assertion":[{"value":"9 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors report no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38"}}