<scp>hiPSC</scp> ‐Derived Astrocytes From Individuals With Schizophrenia Induce a Dystrophic Phenotype in Microglial‐Like Cells

Neuroinflammation, particularly astrocyte reactivity, is increasingly linked to schizophrenia (SCZ). Yet, the crosstalk between astrocytes and microglia in SCZ, especially under pro-inflammatory conditions, remains unclear. Here, we employed human induced-pluripotent stem cells to compare how astrocytes from five age-matched individuals with SCZ and five neurotypical controls, upon stimulation with TNF-α, affected microglial biology. TNF-α stimulation of SCZ astrocytes, relative to their control counterparts, triggered increased mRNA expression of pro-inflammatory cytokines and CX3CL1. Interestingly, transcriptomic and gene set enrichment analyses revealed that reactive SCZ astrocytes promoted the downregulation of biological processes associated with immune cell proliferation and activation, phagocytosis, and cell migration in induced microglial-like cells (iMGs). Under such conditions, iMGs assumed a dystrophic/senescent-like phenotype, which was associated with accelerated transcriptional aging. Functional validations showed that TNF-α-stimulated SCZ astrocytes promoted reduced synaptoneurosomes phagocytosis by iMGs. Interestingly, while both reactive control and SCZ astrocytes were capable of inducing significant microglial migration in a CX3CR1-dependent manner, TNF-α-stimulated SCZ astrocytes failed to promote greater iMG chemotaxis, compared with their stimulated control counterparts, despite secreting more than twice as much CX3CL1. This was likely due to SCZ astrocytes triggering reduction in CX3CR1 plasma membrane levels in iMGs. Altogether, these findings suggest that astrocytes contribute to SCZ pathology by altering normal microglial function and inducing a dystrophic phenotype.