‘Disease in a dish’ study of progressive MS finds critical role for unusual type of brain cell

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"... To model what is happening in the disease, researchers ... took skin cells from patients with progressive MS and reprogrammed them into induced neural stem cells (iNSCs), an immature type of cell capable of dividing and differentiating into various types of brain cells.

Using this ‘disease in a dish’ approach, the team observed that a subset of the cultured brain cells was somehow reverting to an earlier developmental stage, transforming into an unusual cell type known as radial glia-like (RG-like) cells. Notably, these cells were highly specific and appeared approximately six times more frequently in iNSC lines derived from individuals with progressive MS compared to controls. As a result, they were designated as disease-associated RG-like cells (DARGs). ...

Unexpectedly, DARGs not only revert to an ‘infant’ state but also display hallmark features of premature aging, or senescence.

These newly identified DARGs possess a distinctive epigenetic profile—patterns of chemical modifications that regulate gene activity—although the factors influencing this epigenetic landscape remain unclear. These modifications contribute to an exaggerated response to interferons, the immune system’s ‘alarm signals,’ which may help explain the high levels of inflammation observed in MS. ..."

From the highlights and abstract:

"Highlights

• Human iNSCs maintain epigenetic age with high fidelity

• PMS fibroblasts and iNSCs share hypomethylated genes driving IFN signaling

• PMS iNSCs harbor senescent, IFN-responsive RG-like cells that promote inflammation

• Non-neurogenic senescent DARGs are found in lesions of people with PMS

Summary

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."

‘Disease in a dish’ study of progressive MS finds critical role for unusual type of brain cell | University of Cambridge "Scientists have identified an unusual type of brain cell that may play a vital role in progressive multiple sclerosis (MS), likely contributing to the persistent inflammation characteristic of the disease."

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

Graphical abstract