Schizophrenia endothelial cells exhibit higher permeability and altered angiogenesis patterns in patient-derived organoids

Schizophrenia endothelial cells exhibit higher permeability and altered angiogenesis patterns in patient-derived organoids

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Abstract Schizophrenia (SCZ) is a complex neurodevelopmental disorder characterized by the manifestation of psychiatric symptoms in early adulthood.While many research avenues into the origins of SCZ during D-Sub/Serial brain development have been explored, the contribution of endothelial/vascular dysfunction to the disease remains largely elusive.To model the neuropathology of SCZ during early critical periods of brain development, we utilized patient-derived induced pluripotent stem cells (iPSCs) to generate 3D cerebral organoids and define cell-specific signatures of disease.Single-cell RNA sequencing revealed that while SCZ organoids were similar in their macromolecular diversity to organoids generated from healthy controls (CTRL), SCZ organoids exhibited a higher percentage of endothelial cells when normalized to total cell numbers.Additionally, when compared to CTRL, differential gene expression analysis revealed a significant enrichment in genes that function in vessel formation, vascular regulation, and inflammatory response in SCZ endothelial cells.

In line with these findings, data from 23 donors demonstrated that PECAM1+ microvascular vessel-like structures were increased in length and number in SCZ organoids in comparison to CTRL organoids.Furthermore, we report that patient-derived endothelial cells Lighter Socket Power Adaptor displayed higher paracellular permeability, implicating elevated vascular activity.Collectively, our data identified altered gene expression patterns, vessel-like structural changes, and enhanced permeability of endothelial cells in patient-derived models of SCZ.Hence, brain microvascular cells could play a role in the etiology of SCZ by modulating the permeability of the developing blood brain barrier (BBB).