Patient-derived stem cell models of brain endothelial-neuron interactions in early course psychosis.

Authors

Deniz Altunsu, Cemal Demirlek, Jennifer Nicholson, Brendan Stiltner, Rebekah Trotti, Nicolas Raymond, Yukyeong Lee, Rufuto Rahman, William Stone, Rakesh Karmacharya, Paulo Lizano

Published in

Frontiers in psychiatry. Volume 17. Pages 1873300. Epub Sep 29, 2026.

Abstract

Early-course psychosis (ECP) exhibits marked heterogeneity in illness trajectories, with a substantial subset of individuals developing progressive symptomatic, cognitive, and functional decline. Although growing evidence implicates blood-brain barrier (BBB) and neurovascular unit (NVU) dysfunction in psychosis spectrum disorders, direct links between longitudinal clinical trajectories and disease-related cellular phenotypes remain insufficiently characterized.
This protocol describes a standardized stem cell-based framework to model BBB and NVU dysfunction in ECP using induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) within a longitudinally characterized clinical cohort. The approach integrates donor-specific ex vivo cellular assays with repeated clinical, cognitive, and functional assessments for up to 5 years. Procedures are detailed for iPSC reprogramming from PBMCs, differentiation of iPSCs to brain microvascular endothelial cells (BMECs) and cortical neurons, and functional assessment of BBB integrity using trans-endothelial electrical resistance (TEER), paracellular permeability, and tight junction protein expression. NVU effects are examined by exposing cortical neurons to BMEC-conditioned media under matched and cross-culture conditions, with quantification of dendritic spine morphology, synaptic puncta, and neuronal activity using micro-electrode arrays. The protocol further incorporates modular mechanistic perturbations, including pharmacological and genetic modulation of matrix metalloproteinase 1 (MMP1), tumor necrosis factor alpha (TNFα)-related signaling, and evaluation of antipsychotic effects on barrier function.
Ethical approval and informed consent for this study was obtained and the findings will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences.

PMID:
42871576
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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