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

Abstract

Schizophrenia (SZ) is a complex neuropsychiatric disorder, affecting 1% of the world population. Long-standing clinical observations and molecular data have pointed out 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 retaining the patient's unique genetic signature. Previously, we reported a VEGF-A signaling impairment in SZ-hiPSC derived neural lineages leading to a 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 secretome 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 that traces schizophrenia origins to brain development and BBB dysfunction.

Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity

“…In this regard, one can see parallels between inflammatory processes in autism and another genetically related developmental disorder, schizophrenia (SCZ) [ 155 , 156 ] In SCZ, inflammatory markers are associated with cortical expansion and impaired blood brain barrier function which correlates with symptom severity [ 157 , 158 ]. Using human induced pluripotent stem cells, SCZ-derived brain endothelial cells have decreased vasculogenesis and permeability, and decreased ZO-1 expression (tight junction protein) with altered cellular localization in the cytoplasm [ 159 ]. These data suggest that both the expression of gene variants of signaling pathways (protein kinases C, G, and A, RhoA, PI3/Akt, and Wnt) which control BBB function in patients and investigation of the disrupted pathways in autism may yield druggable targets [ 160 ].…”

It takes two to tango: Widening our understanding of the onset of schizophrenia from a neuro-angiogenic perspective

“…From these pathways, the NOTCH and WNT pathways are described as having variants in several of their pathway components, increasing the risk of developing the disease. In addition to their well-known role in neurodevelopment, these pathways are important regulators of angiogenesis, a process that is proposed to be downregulated in SZ patients ( Lopes et al, 2015 ; Katsel et al, 2017 ; Casas et al, 2018 ; Casas et al, 2022 ).…”

“…This deficiency in VEGFA signaling has also been corroborated by in vitro SZ hiPSC modeling using NSC. Interestingly, brain microvascular EC derived from SZ-hiPSC have a decreased angiogenic response when stimulated with VEGFA ( Casas et al, 2018 ; Casas et al, 2022 ). However, VEGF protein levels in the superior temporal gyrus (STG) are not significantly different between SZ and control groups ( Izumi et al, 2021 ).…”

Involvement of an Aberrant Vascular System in Neurodevelopmental, Neuropsychiatric, and Neuro-Degenerative Diseases

“…Disruption of the BBB has been documented in schizophrenia, suggesting an association between BBB hyperpermeability and the pathogenesis of schizophrenia [ 63 , 64 , 65 , 66 , 67 ]. In an in vitro study using patient-derived ECs, human iPSCs consistently revealed an intrinsic failure in brain microvascular endothelial-like cells of patients with schizophrenia, thereby affecting proper angiogenesis and the BBB function, which may contribute to altered neurovascular crosstalk during schizophrenia [ 68 ]. Furthermore, epidemiological findings suggest that the risk of certain types of cancer, such as respiratory cancer, is significantly lower in patients with schizophrenia than in those without schizophrenia [ 69 , 70 , 71 , 72 , 73 , 74 ].…”