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

Multiple sclerosis (MS) is considered an inflammatory and neurodegenerative disease of the central nervous system, typically resulting in significant neurological disability that worsens over time. While considerable 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 the largest reported collection of iPSC lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that iPSC-derived cultures from people with primary progressive MS contained fewer oligodendrocytes. Moreover, iPSC-oligodendrocyte lineage cells and astrocytes from people with MS showed increased expression of immune and inflammatory genes that match those of glial cells 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.

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 some of these claims and 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.