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Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders

Molecular Psychiatry volume 28, pages 3698–3708 (2023)Cite this article

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Abstract

Although there is convergent evidence for blood-brain barrier (BBB) dysfunction and peripheral inflammation in schizophrenia (SZ) and bipolar disorder (BD), it is unknown whether BBB deficits are intrinsic to brain microvascular endothelial cells (BMECs) or arise via effects of peripheral inflammatory cytokines. We examined BMEC function using stem cell-based models to identify cellular and molecular deficits associated with BBB dysfunction in SZ and BD. Induced pluripotent stem cells (iPSCs) from 4 SZ, 4 psychotic BD and 4 healthy control (HC) subjects were differentiated into BMEC-“like” cells. Gene expression and protein levels of tight junction proteins were assessed. Transendothelial electrical resistance (TEER) and permeability were assayed to evaluate BBB function. Cytokine levels were measured from conditioned media. BMECs derived from human iPSCs in SZ and BD did not show differences in BBB integrity or permeability compared to HC BMECs. Outlier analysis using TEER revealed a BBB-deficit (n = 3) and non-deficit (n = 5) group in SZ and BD lines. Stratification based on BBB function in SZ and BD patients identified a BBB-deficit subtype with reduced barrier function, tendency for increased permeability to smaller molecules, and decreased claudin-5 (CLDN5) levels. BMECs from the BBB-deficit group show increased matrix metallopeptidase 1 (MMP1) activity, which correlated with reduced CLDN5 and worse BBB function, and was improved by tumor necrosis factor α (TNFα) and MMP1 inhibition. These results show potential deficits in BMEC-like cells in psychotic disorders that result in BBB disruption and further identify TNFα and MMP1 as promising targets for ameliorating BBB deficits.

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Fig. 1: Human iPSC-derived BMECs from SZ patients demonstrate aberrant barrier function in a BBB model.
Fig. 2: A psychosis subgroup shows extensive BBB leakage.
Fig. 3: MMP1 secreted by SZ BMECs impairs BBB function.
Fig. 4: Inhibition of MMP1 and TNFα restores BBB function.

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Data availability

Data as well as data cleaning are available upon request to the corresponding author.

Code availability

Analysis code is available upon request to the corresponding author.

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Acknowledgements

This work was supported by a National Institute of Mental Health Biobehavioral Research Awards for Innovative New Scientists (BRAINS) Award R01MH113858 (to RK), the National Institutes of Health Award KL2 TR002542 (PL), the Stuart T. Hauser Research Training Program in Biological and Social Psychiatry T32 MH 016259 (SS). the National Institute of Mental Health Clinical Scientist Development Award K08MH086846 (to RK), the Sydney R Baer Jr Foundation Grant (to PL), the One Mind Bipolar Disorders Award (to PL), the Doris Duke Charitable Foundation Clinical Scientist Development Award (to RK), the Ryan Licht Sang Bipolar Foundation (to RK), the Phyllis & Jerome Lyle Rappaport Foundation (to RK), the Harvard Stem Cell Institute (to RK) and by Steve Willis and Elissa Freud (to RK). We would like to thank Dr. Donna McPhie and Dr. Bruce Cohen for providing fibroblasts that were used to generate iPSCs for this study.

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  1. These authors contributed equally: Paulo Lizano, Sovannarath Pong.

Authors and Affiliations

  1. Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Paulo Lizano, Sovannarath Pong & Deepthi Bannai

  2. Division of Translational Neuroscience, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Paulo Lizano, Sovannarath Pong & Deepthi Bannai

  3. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Paulo Lizano, Sovannarath Pong, Stephanie Santarriaga & Rakesh Karmacharya

  4. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Paulo Lizano, Stephanie Santarriaga & Rakesh Karmacharya

  5. Chemical Biology and Therapeutic Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Stephanie Santarriaga & Rakesh Karmacharya

  6. Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, MA, USA

    Rakesh Karmacharya

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Contributions

PL adapted and optimized the differentiation protocol for deriving BMECs, as well as designing, conducting, analyzing, and interpreting the results. PL also drafted and edited the manuscript. SP conducted the experiments and helped with the experimental design. SP conducted the data analyses. SS assisted with experimental design, analyses, and proofreading the manuscript. RK provided the cell lines used for this experiment, as well as assisting in the experimental design, analyses, and drafting of the manuscript.

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Correspondence to Paulo Lizano or Rakesh Karmacharya.

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Lizano, P., Pong, S., Santarriaga, S. et al. Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders. Mol Psychiatry 28, 3698–3708 (2023). https://doi.org/10.1038/s41380-023-02255-0

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