Spatially-restricted inflammation-induced senescent-like glia in multiple sclerosis and patient-derived organoids

Francesca Fagiani, Edoardo Pedrini, Maria Sofia Martire, Gaia Gastoldi, Colin Vanden Bulcke, Jing-Ping Lin, Dragan Maric, Elena Brambilla, Francesca Ruffini, Carolina Peri, Peter A. Calabresi, Pietro Maggi, Paola Panina-Bordignon, Gianvito Martino, Daniel S. Reich and Martina Absinta ()
Additional contact information
Francesca Fagiani: IRCCS San Raffaele Scientific Institute
Edoardo Pedrini: IRCCS San Raffaele Scientific Institute
Maria Sofia Martire: IRCCS San Raffaele Scientific Institute
Gaia Gastoldi: IRCCS San Raffaele Scientific Institute
Colin Vanden Bulcke: Université Catholique de Louvain
Jing-Ping Lin: National Institutes of Health
Dragan Maric: National Institutes of Health
Elena Brambilla: IRCCS San Raffaele Hospital
Francesca Ruffini: IRCCS San Raffaele Hospital
Carolina Peri: IRCCS San Raffaele Hospital
Peter A. Calabresi: Johns Hopkins School of Medicine
Pietro Maggi: Université Catholique de Louvain
Paola Panina-Bordignon: IRCCS San Raffaele Hospital
Gianvito Martino: IRCCS San Raffaele Hospital
Daniel S. Reich: National Institutes of Health
Martina Absinta: Humanitas University

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract In multiple sclerosis (MS), chronic compartmentalized inflammation is thought to drive relentless clinical deterioration. Here, we investigate the link between unresolved parenchymal inflammation and cellular senescence in MS progression. Single-cell transcriptomic analysis of human brain tissue reveals an accumulation of senescent-like glial cells in diseased white matter, especially in chronic active lesions, and to a lesser extent in the cortex. Spatial transcriptomics show gradients of senescence-like signatures extending from lesion cores to periplaque regions, alongside rewired cellular networks. Experimental induction of senescence in MS hiPSC-derived neural organoids demonstrates that microglia are especially vulnerable to inflammation-induced senescence, which can be partially rescued by CNS-penetrant anti-inflammatory drugs. At the patient level (n = 466), increased 3T MRI-estimated brain-age is observed, especially in individuals with more than four chronic active lesions. These findings suggest that chronic inflammation might accelerate senescence-like processes, potentially contributing to disease progression, and that its modulation might help limit further propagation.

Date: 2025
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DOI: 10.1038/s41467-025-63371-9

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