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Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization

Molecular Psychiatry volume 28, pages 871–882 (2023)Cite this article

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Abstract

Molecular and functional abnormalities of astrocytes have been implicated in the etiology and pathogenesis of schizophrenia (SCZ). In this study, we examined the proteome, inflammatory responses, and secretome effects on vascularization of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with SCZ. Proteomic analysis revealed alterations in proteins related to immune function and vascularization. Reduced expression of the nuclear factor kappa B (NF-κB) p65 subunit was observed in these astrocytes, with no incremental secretion of cytokines after tumor necrosis factor alpha (TNF-α) stimulation. Among inflammatory cytokines, secretion of interleukin (IL)-8 was particularly elevated in SCZ-patient-derived-astrocyte-conditioned medium (ASCZCM). In a chicken chorioallantoic membrane (CAM) assay, ASCZCM reduced the diameter of newly grown vessels. This effect could be mimicked with exogenous addition of IL-8. Taken together, our results suggest that SCZ astrocytes are immunologically dysfunctional and may consequently affect vascularization through secreted factors.

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Fig. 1: Workflow sketch.
Fig. 2: hiPSC-derived SCZ astrocytes exhibit similar protein markers as compared to CTR and differential regulation of pathways.
Fig. 3: hiPSC-derived SCZ astrocytes inflammatory phenotype and p65 subunit of NF-κB response to TNF-α.
Fig. 4: The secretome of hiPSC-derived SCZ astrocytes and its effect on blood vessel development in the chicken chorioallantoic membrane.
Fig. 5: Regulation of the secretome of hiPSC-derived astrocytes reveal clusters of inflammation-related proteins and increased levels of inflammatory cytokines.
Fig. 6: Conditioned Media from hiPSC-derived SCZ astrocytes and Interleukin 8 increased the number and reduced the caliber of vessels in the chicken chorioallantoic membrane.

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Data availability

The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository [94] with the identifiers PXD031650 and PXD031640.

References

  1. Kahn RS, Sommer IE, Murray RM, Meyer-Lindenberg A, Weinberger DR, Cannon TD, et al. Schizophrenia. Nat Rev Dis Prim. 2015;1:15067.

    Article  Google Scholar 

  2. Tandon R, Gaebel W, Barch DM, Bustillo J, Gur RE, Heckers S, et al. Definition and description of schizophrenia in the DSM-5. Schizophr Res. 2013;150:3–10.

    Article  Google Scholar 

  3. Limosin F. Neurodevelopmental and environmental hypotheses of negative symptoms of schizophrenia. BMC Psychiatry. 2014;14:88.

    Article  Google Scholar 

  4. Murray RM, Bhavsar V, Tripoli G, Howes O. 30 Years on: how the neurodevelopmental hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis. Schizophr Bull. 2017;43:1190–6.

    Article  Google Scholar 

  5. Stahl SM. Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate. CNS Spectr. 2018;23:187–91.

    Article  Google Scholar 

  6. Zamanpoor M. Schizophrenia in a genomic era: a review from the pathogenesis, genetic and environmental etiology to diagnosis and treatment insights. Psychiatr Genet. 2020;30:1–9.

    Article  Google Scholar 

  7. Buckley PF. Neuroinflammation and schizophrenia. Curr Psychiatry Rep. 2019;21:72.

    Article  Google Scholar 

  8. Kroken RA, Sommer IE, Steen VM, Dieset I, Johnsen E. Constructing the immune signature of schizophrenia for clinical use and research; an integrative review translating descriptives into diagnostics. Front Psychiatry. 2018;9:753.

    Article  Google Scholar 

  9. Kirkley KS, Popichak KA, Afzali MF, Legare ME, Tjalkens RB. Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity. J Neuroinflammation. 2017;14:99.

    Article  Google Scholar 

  10. Norden DM, Fenn AM, Dugan A, Godbout JP. TGFbeta produced by IL-10 redirected astrocytes attenuates microglial activation. Glia. 2014;62:881–95.

    Article  Google Scholar 

  11. Osipova ED, Semyachkina-Glushkovskaya OV, Morgun AV, Pisareva NV, Malinovskaya NA, Boitsova EB, et al. Gliotransmitters and cytokines in the control of blood-brain barrier permeability. Rev Neurosci. 2018;29:567–91.

    Article  CAS  Google Scholar 

  12. Matos M, Shen HY, Augusto E, Wang Y, Wei CJ, Wang YT, et al. Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia. Biol Psychiatry. 2015;78:763–74.

    Article  CAS  Google Scholar 

  13. Shan D, Lucas EK, Drummond JB, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE. Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia. Schizophr Res. 2013;144:1–8.

    Article  Google Scholar 

  14. Barley K, Dracheva S, Byne W. Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder. Schizophr Res. 2009;112:54–64.

    Article  Google Scholar 

  15. Markova E, Markov I, Revishchin A, Okhotin V, Sulimov G. 3-D Golgi and image analysis of the olfactory tubercle in schizophrenia. Anal Quant Cytol Histol. 2000;22:178–82.

    CAS  Google Scholar 

  16. Rothermundt M, Ohrmann P, Abel S, Siegmund A, Pedersen A, Ponath G, et al. Glial cell activation in a subgroup of patients with schizophrenia indicated by increased S100B serum concentrations and elevated myo-inositol. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:361–4.

    Article  CAS  Google Scholar 

  17. Falkai P, Honer WG, David S, Bogerts B, Majtenyi C, Bayer TA. No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study. Neuropathol Appl Neurobiol. 1999;25:48–53.

    Article  CAS  Google Scholar 

  18. Perrone-Bizzozero NI, Sower AC, Bird ED, Benowitz LI, Ivins KJ, Neve RL. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc Natl Acad Sci USA. 1996;93:14182–7.

    Article  CAS  Google Scholar 

  19. Williams M, Pearce RK, Hirsch SR, Ansorge O, Thom M, Maier M. Fibrillary astrocytes are decreased in the subgenual cingulate in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2014;264:357–62.

    Article  Google Scholar 

  20. Boerrigter D, Weickert TW, Lenroot R, O’Donnell M, Galletly C, Liu D, et al. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation. 2017;14:188.

    Article  Google Scholar 

  21. Hua J, Brandt AS, Lee S, Blair NIS, Wu Y, Lui S, et al. Abnormal grey matter arteriolar cerebral blood volume in schizophrenia measured with 3D inflow-based vascular-space-occupancy MRI at 7T. Schizophr Bull. 2017;43:620–32.

    Google Scholar 

  22. Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry. 2000;5:142–9.

    Article  CAS  Google Scholar 

  23. Saia-Cereda VM, Cassoli JS, Schmitt A, Falkai P, Nascimento JM, Martins-de-Souza D. Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains. Eur Arch Psychiatry Clin Neurosci. 2015;265:601–12.

    Article  Google Scholar 

  24. Sivagnanasundaram S, Crossett B, Dedova I, Cordwell S, Matsumoto I. Abnormal pathways in the genu of the corpus callosum in schizophrenia pathogenesis: a proteome study. Proteom Clin Appl. 2007;1:1291–305.

    Article  CAS  Google Scholar 

  25. Nesvaderani M, Matsumoto I, Sivagnanasundaram S. Anterior hippocampus in schizophrenia pathogenesis: molecular evidence from a proteome study. Aust N Z J Psychiatry. 2009;43:310–22.

    Article  Google Scholar 

  26. Davalieva K, Maleva Kostovska I, Dwork AJ. Proteomics research in schizophrenia. Front Cell Neurosci. 2016;10:18.

    Article  Google Scholar 

  27. Nascimento JM, Martins-de-Souza D. The proteome of schizophrenia. NPJ Schizophr. 2015;1:14003.

    Article  Google Scholar 

  28. Steiner J, Bernstein HG, Bielau H, Farkas N, Winter J, Dobrowolny H, et al. S100B-immunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study. J Psychiatr Res. 2008;42:868–76.

    Article  Google Scholar 

  29. Goldsmith DR, Rapaport MH. Inflammation and negative symptoms of schizophrenia: implications for reward processing and motivational deficits. Front Psychiatry. 2020;11:46.

    Article  Google Scholar 

  30. Yang AC, Tsai SJ. New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci. 2017;18:1689.

  31. Ahmad R, Sportelli V, Ziller M, Spengler D, Hoffmann A. Tracing early neurodevelopment in schizophrenia with induced pluripotent stem cells. Cells 2018;7:140.

  32. Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev. 2011;35:878–93.

    Article  CAS  Google Scholar 

  33. Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry. 2015;20:361–8.

    Article  CAS  Google Scholar 

  34. Ni P, Noh H, Park GH, Shao Z, Guan Y, Park JM, et al. iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function. Mol Psychiatry. 2020;25:2873–88.

  35. Paulsen Bda S, de Moraes Maciel R, Galina A, Souza da Silveira M, dos Santos Souza C, Drummond H, et al. Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient. Cell Transplant. 2012;21:1547–59.

    Article  Google Scholar 

  36. Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L, et al. Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell. 2017;21:195–208.e6.

    Article  CAS  Google Scholar 

  37. Akkouh IA, Ueland T, Hansson L, Inderhaug E, Hughes T, Steen NE, et al. Decreased IL-1beta-induced CCL20 response in human iPSC-astrocytes in schizophrenia: Potential attenuating effects on recruitment of regulatory T cells. Brain Behav Immun. 2020;87:634–44.

  38. Casas BS, Vitoria G, do Costa MN, Madeiro da Costa R, Trindade P, Maciel R, et al. hiPSC-derived neural stem cells from patients with schizophrenia induce an impaired angiogenesis. Transl Psychiatry. 2018;8:48.

    Article  Google Scholar 

  39. Trindade P, Loiola EC, Gasparotto J, Ribeiro CT, Cardozo PL, Devalle S, et al. Short and long TNF-alpha exposure recapitulates canonical astrogliosis events in human-induced pluripotent stem cells-derived astrocytes. Glia 2020;68:1396–409.

    Article  Google Scholar 

  40. Nascimento JM, Saia-Cereda VM, Sartore RC, da Costa RM, Schitine CS, Freitas HR, et al. Human cerebral organoids and fetal brain tissue share proteomic similarities. Front Cell Dev Biol. 2019;7:303.

    Article  Google Scholar 

  41. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.

    Article  Google Scholar 

  42. Fabregat A, Jupe S, Matthews L, Sidiropoulos K, Gillespie M, Garapati P, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2018;46:D649–55.

    Article  CAS  Google Scholar 

  43. Kanehisa M. Chemical and genomic evolution of enzyme-catalyzed reaction networks. FEBS Lett. 2013;587:2731–7.

    Article  CAS  Google Scholar 

  44. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–13.

    Article  CAS  Google Scholar 

  45. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.

    Article  CAS  Google Scholar 

  46. Metsalu T, Vilo J. ClustVis: a web tool for visualizing clustering of multivariate data using principal component analysis and heatmap. Nucleic Acids Res. 2015;43:W566–70.

    Article  CAS  Google Scholar 

  47. Barbar L, Jain T, Zimmer M, Kruglikov I, Sadick JS, Wang M, et al. CD49f is a novel marker of functional and reactive human iPSC-derived astrocytes. Neuron. 2020;107:436–53.e12.

    Article  CAS  Google Scholar 

  48. Ramjeesingh R, Leung R, Siu CH. Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1. FASEB J. 2003;17:1292–4.

    Article  CAS  Google Scholar 

  49. Comer AL, Carrier M, Tremblay ME, Cruz-Martin A. The inflamed brain in schizophrenia: the convergence of genetic and environmental risk factors that lead to uncontrolled neuroinflammation. Front Cell Neurosci. 2020;14:274.

    Article  CAS  Google Scholar 

  50. McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG. Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. Transl Psychiatry. 2011;1:e36.

    Article  CAS  Google Scholar 

  51. Mokhtari R, Lachman HM. The major histocompatibility complex (MHC) in schizophrenia: a review. J Clin Cell Immunol. 2016;7:479.

  52. Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E. Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry. 2007;7:46.

    Article  Google Scholar 

  53. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460:744–7.

    Article  CAS  Google Scholar 

  54. Roussos P, Katsel P, Davis KL, Giakoumaki SG, Lencz T, Malhotra AK, et al. Convergent findings for abnormalities of the NF-kappaB signaling pathway in schizophrenia. Neuropsychopharmacology. 2013;38:533–9.

    Article  CAS  Google Scholar 

  55. Murphy CE, Walker AK, Weickert CS. Neuroinflammation in schizophrenia: the role of nuclear factor kappa B. Transl Psychiatry. 2021;11:528.

    Article  CAS  Google Scholar 

  56. Dresselhaus EC, Meffert MK. Cellular Specificity of NF-kappaB Function in the Nervous System. Front Immunol. 2019;10:1043.

    Article  CAS  Google Scholar 

  57. Frydecka D, Krzystek-Korpacka M, Lubeiro A, Stramecki F, Stanczykiewicz B, Beszlej JA, et al. Profiling inflammatory signatures of schizophrenia: a cross-sectional and meta-analysis study. Brain Behav Immun. 2018;71:28–36.

    Article  Google Scholar 

  58. Trepanier MO, Hopperton KE, Mizrahi R, Mechawar N, Bazinet RP. Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review. Mol Psychiatry. 2016;21:1009–26.

    Article  CAS  Google Scholar 

  59. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 2018;362:eaat8127.

  60. Dietz AG, Goldman SA, Nedergaard M. Glial cells in schizophrenia: a unified hypothesis. Lancet Psychiatry. 2020;7:272–81.

    Article  Google Scholar 

  61. Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature 2005;436:193–200.

    Article  CAS  Google Scholar 

  62. Eichmann A, Le Noble F, Autiero M, Carmeliet P. Guidance of vascular and neural network formation. Curr Opin Neurobiol. 2005;15:108–15.

    Article  CAS  Google Scholar 

  63. Assous M, Martinez E, Eisenberg C, Shah F, Kosc A, Varghese K, et al. Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice. J Neurosci. 2019;39:8845–59.

    Article  Google Scholar 

  64. Gelfand MV, Hagan N, Tata A, Oh WJ, Lacoste B, Kang KT, et al. Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding. Elife 2014;3:e03720.

    Article  Google Scholar 

  65. Biswas S, Cottarelli A, Agalliu D. Neuronal and glial regulation of CNS angiogenesis and barriergenesis. Development 2020;147:dev182279.

  66. Shariq M, Sahasrabuddhe V, Krishna S, Radha S, Nruthyathi, Bellampalli R, et al. Adult neural stem cells have latent inflammatory potential that is kept suppressed by Tcf4 to facilitate adult neurogenesis. Sci Adv. 2021;7:eabf5606.

  67. Carrier M, Guilbert J, Levesque JP, Tremblay ME, Desjardins M. Structural and functional features of developing brain capillaries, and their alteration in schizophrenia. Front Cell Neurosci. 2020;14:595002.

    Article  CAS  Google Scholar 

  68. Katsel P, Roussos P, Pletnikov M, Haroutunian V. Microvascular anomaly conditions in psychiatric disease. Schizophrenia - angiogenesis connection. Neurosci Biobehav Rev. 2017;77:327–39.

    Article  Google Scholar 

  69. Uranova N, Zimina I, Vikhreva O, Rachmanova V, Klintsova A, Orlovskaya D. Reduced capillary density in the prefrontal cortex in schizophrenia. Am J Med Sci Med. 2013;1:45–51.

    Google Scholar 

  70. Hosak L, Zeman T, Studnicka J, Stepanov A, Ustohal L, Michalec M, et al. Retinal arteriolar and venular diameters are widened in patients with schizophrenia. Psychiatry Clin Neurosci. 2020;74:619–21.

    Article  Google Scholar 

  71. Meier MH, Shalev I, Moffitt TE, Kapur S, Keefe RS, Wong TY, et al. Microvascular abnormality in schizophrenia as shown by retinal imaging. Am J Psychiatry. 2013;170:1451–9.

    Article  Google Scholar 

  72. Korann V, Appaji A, Jacob A, Devi P, Nagendra B, Chako DM, et al. Association between retinal vascular caliber and brain structure in schizophrenia. Asian J Psychiatr. 2021;61:102707.

    Article  Google Scholar 

  73. Kindler J, Schultze-Lutter F, Hauf M, Dierks T, Federspiel A, Walther S, et al. Increased striatal and reduced prefrontal cerebral blood flow in clinical high risk for psychosis. Schizophr Bull. 2018;44:182–92.

    Article  Google Scholar 

  74. Lahti AC, Holcomb HH, Medoff DR, Weiler MA, Tamminga CA, Carpenter WT Jr. Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task. Am J Psychiatry. 2001;158:1797–808.

    Article  CAS  Google Scholar 

  75. Liu F, Zhuo C, Yu C. Altered cerebral blood flow covariance network in schizophrenia. Front Neurosci. 2016;10:308.

    Article  Google Scholar 

  76. Paradiso S, Andreasen NC, Crespo-Facorro B, O’Leary DS, Watkins GL, Boles Ponto LL, et al. Emotions in unmedicated patients with schizophrenia during evaluation with positron emission tomography. Am J Psychiatry. 2003;160:1775–83.

    Article  Google Scholar 

  77. Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004;161:889–95.

    Article  Google Scholar 

  78. Ellman LM, Deicken RF, Vinogradov S, Kremen WS, Poole JH, Kern DM, et al. Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophr Res. 2010;121:46–54.

    Article  Google Scholar 

  79. Zakharyan R, Boyajyan A. Inflammatory cytokine network in schizophrenia. World J Biol Psychiatry. 2014;15:174–87.

    Article  Google Scholar 

  80. An HM, Tan YL, Shi J, Wang ZR, Soars JC, Wu JQ, et al. Altered IL-2, IL-6 and IL-8 serum levels in schizophrenia patients with tardive dyskinesia. Schizophr Res. 2015;162:261–8.

    Article  Google Scholar 

  81. Dahan S, Bragazzi NL, Yogev A, Bar-Gad M, Barak V, Amital H, et al. The relationship between serum cytokine levels and degree of psychosis in patients with schizophrenia. Psychiatry Res. 2018;268:467–72.

    Article  CAS  Google Scholar 

  82. Zhang XY, Zhou DF, Zhang PY, Wu GY, Cao LY, Shen YC. Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res. 2002;57:247–58.

    Article  Google Scholar 

  83. Taub DD, Anver M, Oppenheim JJ, Longo DL, Murphy WJ. T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo. J Clin Investig. 1996;97:1931–41.

    Article  CAS  Google Scholar 

  84. Ryu JK, Cho T, Choi HB, Jantaratnotai N, McLarnon JG. Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer’s disease. J Neuroinflammation. 2015;12:144.

    Article  Google Scholar 

  85. Kuzior H, Fiebich BL, Yousif NM, Saliba SW, Ziegler C, Nickel K, et al. Increased IL-8 concentrations in the cerebrospinal fluid of patients with unipolar depression. Compr Psychiatry. 2020;102:152196.

    Article  Google Scholar 

  86. Pieper C, Pieloch P, Galla HJ. Pericytes support neutrophil transmigration via interleukin-8 across a porcine co-culture model of the blood-brain barrier. Brain Res. 2013;1524:1–11.

    Article  CAS  Google Scholar 

  87. Kossmann T, Stahel PF, Lenzlinger PM, Redl H, Dubs RW, Trentz O, et al. Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production. J Cereb Blood Flow Metab. 1997;17:280–9.

    Article  CAS  Google Scholar 

  88. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol. 2003;170:3369–76.

    Article  CAS  Google Scholar 

  89. Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK. Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis. 2005;8:63–71.

    Article  CAS  Google Scholar 

  90. Garcia-Rizo C, Casanovas M, Fernandez-Egea E, Oliveira C, Meseguer A, Cabrera B, et al. Blood cell count in antipsychotic-naive patients with non-affective psychosis. Early Inter Psychiatry. 2019;13:95–100.

    Article  Google Scholar 

  91. Nunez C, Stephan-Otto C, Usall J, Bioque M, Lobo A, Gonzalez-Pinto A, et al. Neutrophil count is associated with reduced gray matter and enlarged ventricles in first-episode psychosis. Schizophr Bull. 2019;45:846–58.

    Article  Google Scholar 

  92. Karageorgiou V, Milas GP, Michopoulos I. Neutrophil-to-lymphocyte ratio in schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2019;206:4–12.

    Article  Google Scholar 

  93. Zhou X, Wang X, Li R, Yan J, Xiao Y, Li W, et al. Neutrophil-to-lymphocyte ratio is independently associated with severe psychopathology in schizophrenia and is changed by antipsychotic administration: a large-scale cross-sectional retrospective study. Front Psychiatry. 2020;11:581061.

    Article  Google Scholar 

  94. Perez-Riverol Y, Bai J, Bandla C, Garcia-Seisdedos D, Hewapathirana S, Kamatchinathan S, et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 2022;50:D543–52.

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge the contributions on technical support of Fernanda Albuquerque, Gabriela Lopes Vitória, Ismael Carlos da Silva Gomes, Jarek Sochacki, Paulo Baldasso, Mariana Fioramonte, Marcelo do Nascimento Costa and Renata Maciel Santos. This project was sponsored by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul (PRONEX - FAPERGS), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Instituto Nacional de Neurociência Translacional (INNT), Banco Nacional de Desenvolvimento (BNDES), the São Paulo Research Foundation (FAPESP) #2014/21035-0 (JMN), 2017/25588-1 (DMS) and 2019/00098-7 (DMS) and ANID/FONDECYT # 1190083 (VP), CONICYT/ANID Fellowships for Ph.D. #21150781 (BC), in addition to intramural grants from D’Or Institute for Research and Education.

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Author notes

  1. These authors contributed equally: Pablo Trindade, Juliana M. Nascimento.

Authors and Affiliations

  1. Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil

    Pablo Trindade, Juliana Minardi Nascimento, Sylvie Devalle, Daniel Martins-de-Souza & Stevens K. Rehen

  2. Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Pablo Trindade

  3. Departamento de Bioquímica e Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, Brazil

    Juliana Minardi Nascimento & Daniel Martins-de-Souza

  4. Departamento de Biociências, Universidade Federal de São Paulo, Santos, Brazil

    Juliana Minardi Nascimento

  5. Laboratory of Stem Cells & Developmental Biology, Departamento de Biología, Universidad de Chile, Santiago, Chile

    Bárbara S. Casas, Tomás Monteverde & Verónica Palma

  6. Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil

    Juciano Gasparotto

  7. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Camila Tiefensee Ribeiro, José Claudio Fonseca Moreira, Daniel Pens Gelain & Lisiane O. Porciuncula

  8. Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile

    Daniela Sauma

  9. Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP, Brazil

    Daniel Martins-de-Souza

  10. Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, Brazil

    Daniel Martins-de-Souza

  11. Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Stevens K. Rehen

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Contributions

PT, JMN, and SKR conceived and designed the study. PT performed all iPSC-derived cell experiments. JMN performed proteomic experiments, analyses, and interpretation. BSC and TM performed CAM experiments, analyses, and interpreted data. SD performed and analyzed RT-qPCR experiments. JG, CTR, JCFM, and DPG performed and analyzed cytokine secretome data. VP contributed to angiogenesis experiments, analyses, and data interpretation. DMS supervised proteomic experiments and data interpretation. PT, JMN, and LOP interpreted data, wrote, prepared figures, and revised the paper. SKR coordinated the study. All authors revised and contributed to the final version of this paper.

Corresponding authors

Correspondence to Pablo Trindade, Juliana Minardi Nascimento or Stevens K. Rehen.

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Trindade, P., Nascimento, J.M., Casas, B.S. et al. Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization. Mol Psychiatry 28, 871–882 (2023). https://doi.org/10.1038/s41380-022-01830-1

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