Spatially-restricted inflammation-induced senescent-like glia in multiple sclerosis and patient-derived organoids
(2025) Nature Communications — Vol. 16, n° 1, p. 8477 (2025)
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- 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.
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Fagiani, F., Pedrini, E., Martire, M. S., Gastoldi, G., Vanden Bulcke, C., Lin, J.-P., Maric, D., Brambilla, E., Ruffini, F., Peri, C., Calabresi, P. A., Maggi, P., Panina-Bordignon, P., Martino, G., Reich, D. S., & Absinta, M. (2025). Spatially-restricted inflammation-induced senescent-like glia in multiple sclerosis and patient-derived organoids. Nature Communications, 16(1), 8477. https://doi.org/10.1038/s41467-025-63371-9 (Original work published 2025)