尽管关于血脑屏障（BBB）功能障碍和周围炎症在精神分裂症（SZ）和躁郁症（BD）中存在一致的证据，但尚不清楚BBB缺陷是脑微血管内皮细胞（BMEC）固有的还是由于外周炎性细胞因子的影响而产生的。我们利用干细胞为基础的模型检测BMEC功能，以识别与SZ和BD中的BBB功能障碍相关的细胞和分子缺陷。从4个SZ、4个BD和4个健康对照（HC）受试者中诱导多能干细胞（iPSCs），分化出BMEC类细胞。评估紧密连接蛋白的基因表达和蛋白水平。进行跨内皮细胞电阻（TEER）和渗透性测定，评估BBB功能。测量培养基中的细胞因子水平。从SZ和BD中分化的BMECs与HC BMECs相比，未显示出BBB完整性或渗透性的差异。使用TEER进行异常值分析发现SZ和BD系列中存在BBB缺陷（n=3）和非缺陷（n=5）两个组。基于SZ和BD患者BBB功能的分层确定了一种BBB缺陷亚型，其具有降低的屏障功能，对较小分子的渗透性有增加的倾向，并且降低了claudin-5（CLDN5）水平。BBB缺陷组的BMECs显示出增加的基质金属蛋白酶1（MMP1）活性，与CLDN5降低和更差的BBB功能相关，并通过肿瘤坏死因子α（TNFα）和MMP1抑制得到改善。这些结果显示了精神疾病中BMEC类细胞的潜在缺陷，导致BBB破坏，并进一步确定TNFα和MMP1作为改善BBB缺陷的有希望的靶点。©2023年。作者授予Springer Nature Limited独家许可。

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.