Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F25%3A00644100" target="_blank" >RIV/86652036:_____/25:00644100 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60461373:22310/25:43933633

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S089662732500710X" target="_blank" >https://www.sciencedirect.com/science/article/pii/S089662732500710X</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.neuron.2025.09.022" target="_blank" >10.1016/j.neuron.2025.09.022</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Neuron

ISSN

0896-6273

e-ISSN

1097-4199

Svazek periodika

113

Číslo periodika v rámci svazku

24

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

31

Strana od-do

4158-4177

Kód UT WoS článku

001645180400002

EID výsledku v databázi Scopus

2-s2.0-105025230432