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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The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository  with the identifiers PXD031650 and PXD031640.
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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.
The authors declare no competing interests.
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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