Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".