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Schizophrenia-derived hiPSC brain microvascular endothelial-like cells show impairments in angiogenesis and blood–brain barrier function

Molecular Psychiatry volume 27, pages 3708–3718 (2022)Cite this article

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Abstract

Schizophrenia (SZ) is a complex neuropsychiatric disorder, affecting 1% of the world population. Long-standing clinical observations and molecular data have pointed to a possible vascular deficiency that could be acting synergistically with neuronal dysfunction in SZ. As SZ is a neurodevelopmental disease, the use of human-induced pluripotent stem cells (hiPSC) allows disease biology modeling while retaining the patient’s unique genetic signature. Previously, we reported a VEGFA signaling impairment in SZ-hiPSC-derived neural lineages leading to decreased angiogenesis. Here, we present a functional characterization of SZ-derived brain microvascular endothelial-like cells (BEC), the counterpart of the neurovascular crosstalk, revealing an intrinsically defective blood–brain barrier (BBB) phenotype. Transcriptomic assessment of genes related to endothelial function among three control (Ctrl BEC) and five schizophrenia patients derived BEC (SZP BEC), revealed that SZP BEC have a distinctive expression pattern of angiogenic and BBB-associated genes. Functionally, SZP BEC showed a decreased angiogenic response in vitro and higher transpermeability than Ctrl BEC. Immunofluorescence staining revealed less expression and altered distribution of tight junction proteins in SZP BEC. Moreover, SZP BEC’s conditioned media reduced barrier capacities in the brain microvascular endothelial cell line HCMEC/D3 and in an in vivo permeability assay in mice. Overall, our results describe an intrinsic failure of SZP BEC for proper barrier function. These findings are consistent with the hypothesis tracing schizophrenia origins to brain development and BBB dysfunction.

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Fig. 1: SZP BEC have an altered gene expression pattern of angiogenic and BBB-related genes.
Fig. 2: SZP BEC present a lowered response to an angiogenic stimuli.
Fig. 3: SZP BEC exhibit an increased transpermeability.
Fig. 4: SZP BEC CM present a distinct angiogenic profile.
Fig. 5: SZP BEC CM increases vascular permeability.

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Acknowledgements

We thank Dr. Carol San Martin for kindly donating the HCMEC/D3 line. We are grateful to all the Steven Rehen’s laboratory crew, especially to Dr. Livia Goto, Ismael Gomez, and Scarlett Mercante for technical support. We thank Sofía Puvogel and Robert Seitter for critical reading of the manuscript and Dr. Emiliano Molina for technical assistance. Intramural grants provided from the D’Or Institute for Research and Education (IDOR). Funding from ANID Fondecyt # 1190083 and Fondecyt # 1221522 (VP) & Conicyt # 21150781 (BSC).

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Authors and Affiliations

  1. Laboratory of Stem Cells and Developmental Biology, Universidad de Chile, Santiago, Chile

    Bárbara S. Casas, Catalina P. Prieto & Verónica Palma

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

    Gabriela Vitória & Stevens K. Rehen

  3. ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile

    Mariana Casas & Carlos Chacón

  4. Centro de Medicina Regenerativa, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile

    Markus Uhrig, Fernando Ezquer & Marcelo Ezquer

  5. Departamento de Genética, Instituto de Biología, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Stevens K. Rehen

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  1. Bárbara S. Casas
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Contributions

BSC and VP conceived and designed the experiments. BSC, GV, CPP, MC, CC, and MU performed the experiments and/or contributed to data acquisition. BSC and VP analyzed and interpreted the data. BSC wrote the original article. CPP, MC, SKR, FE, ME, and VP critically revised and edited the article. VP, FE, ME, and SR provided resources, and VP was responsable for general supervision. All authors approved the final version of the article.

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Correspondence to Verónica Palma.

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Casas, B.S., Vitória, G., Prieto, C.P. et al. Schizophrenia-derived hiPSC brain microvascular endothelial-like cells show impairments in angiogenesis and blood–brain barrier function. Mol Psychiatry 27, 3708–3718 (2022). https://doi.org/10.1038/s41380-022-01653-0

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