Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time. While progress has been made in defining the immune system's role in MS pathophysiology, the contribution of intrinsic CNS cell dysfunction remains unclear. Here, we generated a collection of induced pluripotent stem cell (iPSC) lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that primary progressive MS-derived cultures contained fewer oligodendrocytes. Moreover, MS-derived oligodendrocyte lineage cells and astrocytes showed increased expression of immune and inflammatory genes, matching those of glia from MS postmortem brains. Thus, iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.

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Déclaration de conflit d'intérêts

Declaration of interests P.J.T. and B.L.L.C. are listed as inventors on issued and pending patent claims covering compositions and methods of enhancing glial cell function. P.J.T. is a co-founder and consultant for Convelo Therapeutics, which has licensed patents from Case Western Reserve University (CWRU). P.J.T. and CWRU retain equity in Convelo Therapeutics. V.F. and L.B. are listed as inventors on issued and pending patent claims covering glial cell generation methods.