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한빛사논문
- 조회19
Neuron, October 10, 2025 | https://doi.org/10.1016/j.neuron.2025.09.022
Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis
Bongsoo Park1,13 ∙ Alexandra M. Nicaise2,13∙ Dimitrios Tsitsipatis3,13 ∙ Liviu Pirvan4 ∙ Daniel Zucha5,6 ∙ Andi Munteanu4,7 ∙ Pranathi Prasad2 ∙ Miguel Larraz Lopez De Novales4 ∙ Cristian Bulgaru4 ∙ Rafael Kollyfas4 ∙ Julia Whitten1 ∙ Cory M. Willis2 ∙ Luka Culig1 ∙ Joseph Llewellyn1 ∙ Rosana-Bristena Ionescu2 ∙ Magdy Mekdad2 ∙ Madalena B.C. Simões-Abade2 ∙ Grzegorz Krzak2 ∙ Jinshui Fan3 ∙ Supriyo De3 ∙ Matthew O. Ellis2,8 ∙ Marta Suarez Cubero9 ∙ Angeliki Spathopoulou9 ∙ Luca Peruzzotti-Jametti2,10 ∙ Tommaso Leonardi11 ∙ Gabriel Balmus2,8,12 ∙ Frank Edenhofer9 ∙ Myriam Gorospe3 ∙ Lukas Valihrach5 ∙ Irina Mohorianu4∙ Stefano Pluchino2,14∙ Isabel Beerman1
1Epigenetics and Stem Cell Unit, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA
2Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge CB2 0AH, UK
3Computational Biology and Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD 21224, USA
4Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK
5Laboratory of Glial Biology and Omics Technologies, Institute of Biotechnology of the Czech Academy of Sciences, 25250 Vestec, Czech Republic
6Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, 16000 Prague, Czech Republic
7Faculty of Computer Science, Alexandru Ioan University, Iasi, Romania
8UK Dementia Research Institute at University of Cambridge, Cambridge, UK
9Institute of Molecular Biology, Department of Genomics, Stem Cell Biology and Regenerative Medicine & CMBI, Leopold-Franzens-University Innsbruck, Innsbruck, Austria
10Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
11Center for Genomic Science of IIT@SEMM, Instituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
12Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, Cluj-Napoca, Romania
13These authors contributed equally
14Lead contact
Correspondence : Alexandra M. Nicaise, Irina Mohorianu, Stefano Pluchino, Isabel Beerman
1Epigenetics and Stem Cell Unit, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA
2Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge CB2 0AH, UK
3Computational Biology and Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD 21224, USA
4Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK
5Laboratory of Glial Biology and Omics Technologies, Institute of Biotechnology of the Czech Academy of Sciences, 25250 Vestec, Czech Republic
6Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, 16000 Prague, Czech Republic
7Faculty of Computer Science, Alexandru Ioan University, Iasi, Romania
8UK Dementia Research Institute at University of Cambridge, Cambridge, UK
9Institute of Molecular Biology, Department of Genomics, Stem Cell Biology and Regenerative Medicine & CMBI, Leopold-Franzens-University Innsbruck, Innsbruck, Austria
10Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
11Center for Genomic Science of IIT@SEMM, Instituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
12Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, Cluj-Napoca, Romania
13These authors contributed equally
14Lead contact
Correspondence : Alexandra M. Nicaise, Irina Mohorianu, Stefano Pluchino, Isabel Beerman
Abstract
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.
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.
논문정보
- Research article
- 2025년 10월 (BRIC 등록일 2025-11-06)
- 국외 연구진
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