Bongsoo Park, Alexandra M. Nicaise, Dimitrios Tsitsipatis, Liviu Pirvan, Daniel Žucha, Andi Munteanu, Pranathi Prasad, Miguel Larraz Lopez De Novales, Cristian Bulgaru, Rafael Kollyfas, Julia Whitten, Cory M. Willis, Luka Čulig, Joseph Llewellyn, Rosana-Bristena Ionescu, Magdy Mekdad, Madalena B C Simões-Abade, Grzegorz Krzak, Jinshui Fan, Supriyo De, Matthew O Ellis, Marta Suarez Cubero, Angeliki Spathopoulou, Luca Peruzzotti‐Jametti, Tommaso Leonardi, Gabriel Balmus, Frank Edenhofer, Myriam Gorospe, Lukáš Valihrach, Irina Mohorianu, Stefano Pluchino, Isabel Beerman
Progressive multiple sclerosis (PMS) involves a persistent, maladaptive inflammatory process with numerous cellular drivers. We generated induced neural stem cells (iNSCs) from patient fibroblasts through a direct reprogramming protocol that preserved their epigenome, which revealed a PMS-specific hypomethylation of lipid metabolism and interferon (IFN) signaling genes. Single-cell multi-omics uncovered a novel, disease-associated radial glia-like cell (DARG) subpopulation in PMS cell lines exhibiting senescence and potent IFN responsiveness driven by specific transcription factors. Functionally, PMS iNSCs induced paracrine senescence and inflammation onto control cells, which was inhibited upon senolytic treatment. We identified in PMS brains a distinct population of senescent, IFN-responsive DARGs that developmentally aligned with the trajectories of iNSCs in vitro and spatially associated with inflammatory glia in chronically active lesions. DARGs may sustain smoldering inflammation, unveiling a previously unrecognized cellular axis that could underpin mechanisms in neurodegeneration. This discovery offers novel insights into disease mechanisms and highlights potential therapeutic targets.