**Progressive Multiple Sclerosis: Revealing Inflammation and Disruption of Repair Mechanisms in the Brain**
In the context of progressive multiple sclerosis (MS), a hidden yet persistent inflammatory process unfolds, especially where the brain’s self-repair capabilities are predominantly hampered. A pioneering study carried out by scientists in Cambridge and the National Institute on Aging has uncovered a novel cellular mechanism that drives this chronic inflammation and neurodegeneration associated with the progressive stage of MS. This investigation highlights a peculiar state of glial cells that seem to be inclined towards inflammation.
The research employed skin cells from patients, reprogrammed into induced neural stem cells (iNSCs), enabling scientists to meticulously map cellular transcripts, chromatin configurations, and DNA methylation. A significant finding included a distinct subset of cells, labeled disease-associated radial glia-like cells, or DARGs. These cells demonstrate an epigenetically dysregulated reaction to interferons and indications of cellular aging. Importantly, while these cells were rare in control groups, they were markedly more abundant in cell lines derived from individuals with progressive MS. Examination of post-mortem brain tissues revealed DARGs located on the periphery and margins of chronically active lesions, amidst active microglia and inflamed astrocytes.
In a healthy brain, radial glia-like cells generally participate in development, facilitating the creation of new neural pathways and differentiating as required. However, the research indicated that within the backdrop of progressive MS, these cells shift into a non-neurogenic, inflammatory state. The integration of multi-omics data unveiled sustained hypomethylation in genes related to the interferon pathway in patient fibroblasts, even following reprogramming. This was accompanied by increased chromatin accessibility at locations of interferon-responsive promoters and enhancers. The alterations clustered around IRF1 and other transcription factors, signifying a cellular preparedness to recognize distress signals from RNA and DNA and respond accordingly.
Functionally, media conditioned by progressive MS iNSCs triggered senescence and interferon signaling in corresponding control cells, leading to diminished cell proliferation and disruption of maintenance pathways such as Notch and Wnt. Spatial data further corroborated this trend, illustrating that elevated DARG activity was concentrated at lesion edges and perilesional white matter. Here, the number of oligodendrocytes dwindles, while microglia saturated with iron and exhibiting a foamy phenotype accumulate, illustrating a vivid depiction where damage gradually spreads outward from lesions.
### Epigenetic Memory and Disease Pathology
A particularly notable aspect of the study is what transpires upstream of the brain: fibroblasts from patients with progressive MS already displayed hypomethylation in genes involved in the interferon response and lipid metabolism. Unlike pathways involving induced pluripotent stem cells (iPSCs), direct reprogramming retained the epigenetic age, preserving disease-associated memory in the derived neural stem cells. This epigenetic memory effectively preps cells for heightened interferon responses and a proclivity towards senescence under duress.
Regulatory network evaluations underscored IRF family members and P53, with single-cell regulon inference emphasizing IRF1 and FOXP2 as crucial components of DARGs. The inclination towards interferon was evident, with significant upticks in genes such as IFIT1 and ISG15, alongside corresponding promoter accessibility. This indicates a system inclined towards interpreting inflammatory alerts over repair mechanisms.
### Therapeutic Implications and Future Directions
From a therapeutic standpoint, the findings reveal potential targets. The application of the senolytic agent ABT-263 on progressive MS iNSCs indicated it did not fully eliminate the inflammatory cluster but helped diminish interferon and senescence signaling while softening the secretome’s toxicity. This unveils a pathway to alleviate lingering inflammation, even if DARGs persist.
For clinical implementation, identifying robust biomarkers and understanding causative factors are imperative. The research offers candidate signatures that could be traceable in tissue samples and biofluids. Moreover, the co-localization of DARGs with lesion areas that predict MS progression provides a vital connection between cellular states and relevant pathology. Upcoming trials seek to define surface targets, validate functional roles in models mimicking lesion rims, and evaluate whether strategies that modulate senescence or antiviral responses can decelerate chronic lesion advancement.
Unresolved questions persist, including whether DARGs arise from mature astrocytes de-differentiating due to chronic stress, or from precursor cells that do not complete a neurogenic process. The influence of viral history and endogenous retroviral activity on priming interferon responses and epigenetic shifts is also being explored. Fortunately, the availability of comprehensive datasets, encompassing bulk RNA sequencing and single-cell RNA and ATAC analyses, serves as a valuable resource for further investigation.
As expressed in a defining statement from the researchers, “Our goal is to create therapies that either rectify DARG dysfunction or eliminate them completely.” For those confronting progressive MS, this research instills hope by identifying a critical determinant.