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Aberrant and sustained activation of microglia is implicated in the progression and severity of multiple sclerosis (MS). However, whether intrinsic alterations in microglial function impact the pathogenesis of this disease remains unclear.

We conducted transcriptomic and functional analyses of microglia-like cells (iMGLs) differentiated from induced pluripotent stem cells (iPSCs) from patients with MS (pwMS) to answer this question.

We generated iPSCs from six pwMS showing increased microglial activity via translocator protein (TSPO)-PET imaging. We demonstrated that the differentiated iMGL transcriptional profile resembled the microglial signature found in MS lesions. Importantly, compared with healthy controls, MS iMGLs presented cell-autonomous differences in their regulation of inflammation, both in the basal state and following inflammatory lipopolysaccharide challenge. Through transcriptomic profiling, we showed that MS iMGLs display increased expression of genes known to be upregulated in MS microglia. Furthermore, upregulated genes in MS iMGLs were associated with immune receptor activation, antigen presentation, and the complement system, with known MS implications. Finally, functional analyses indicated that the transcriptional changes in MS iMGLs corresponded with alterations in the secretion of inflammatory cytokines and chemokines and increased phagocytosis.

Together, our results provide evidence of putative cell-autonomous microglial activation in pwMS and identify transcriptomic and functional changes that recapitulate the phenotypes observedin vivoin microglia from pwMS. These findings indicate that MS disease-specific iPSCs are valuable tools for studying disease-specific microglial activationin vitroand highlight microglia as potential therapeutic targets in MS.