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

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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Publication Details

Journal
Nature Communications
Published
2025-09-26
DOI
https://doi.org/10.1038/s41467-025-63371-9
Citations
5
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
4.03
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article

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

Martina Absinta, Pietro Maggi, Edoardo Pedrini, Colin Vanden Bulcke et al.
5 citations
Nature Communications
RNA regulation and disease
4.03
article

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

Martina Absinta, Pietro Maggi, Edoardo Pedrini, Colin Vanden Bulcke, Maria Sofia Martire, Gianvito Martino, Francesca Fagiani, Daniel S. Reich, Francesca Ruffini, Paola Panina‐Bordignon, Jing‐Ping Lin, Peter A. Calabresi, Carolina Peri, Dragan Maric, Elena Brambilla, Gaia Gastoldi
article en
5 citations

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.

Nature CommunicationsVol. 16(1)
National Institutes of Health (US), Humanitas University (IT), Johns Hopkins University (US), Vita-Salute San Raffaele University (IT), Johns Hopkins Medicine (US), National Institute of Neurological Disorders and Stroke (US), IRCCS Ospedale San Raffaele (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), IRCCS Humanitas Research Hospital (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), UCLouvain (BE)
Openalex Percentile: Top 6%
RNA regulation and disease
4.03
DOIOpen Access PDFOpenAlex
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