Exploring radial glia-like cell neurotoxicity in progressive multiple sclerosis

Summary

Brain regeneration is significantly reduced in Progressive Multiple Sclerosis (pwPMS) compared to active MS. Cellular stress and senescence in neurotoxic astrocytes and microglia exacerbate neurodegeneration and accelerate brain aging. Current animal models poorly replicate human MS features, necessitating investigation into senescent cells and processes like smouldering inflammation in pwPMS.

We hypothesize that accelerated brain aging, smouldering inflammation, and disease severity in PMS are interconnected through cellular senescence. Senescent cells, accumulating with aging, create a pro-inflammatory and neurotoxic environment via paracrine mechanisms.

This project focuses on Disease-Associated Radial Glia (DARGs)-like cells, which undergo adaptive reprogramming upon chronic brain inflammation, and exhibit a de-differentiated, inflammatory, and senescent phenotype. We aim to elucidate how paracrine senescence in DARGs drives MS progression.

Preliminary data indicate that senescence significantly impacts PMS pathology. NPCs from pwPMS iPSCs exhibit senescence markers and impaired oligodendrocyte maturation, reversible with rapamycin. Patient fibroblast-derived iNSCs show gene hypomethylation linked to lipid metabolism and IFN signaling. Single-cell sequencing revealed inflammatory, senescent DARGs, and HMG-CoA reductase inhibition reduces paracrine neurotoxicity, suggesting therapeutic potential.

Project aims

This project utilizes patient-derived cell lines and human iNSC-hybrid brain organoids to model MS pathobiology in vitro. By grafting control and PMS iNSCs into brain organoids, we study senescence-associated dysfunction. Techniques include single-cell lipidomics, barcoded viral tracing, and spatial biology to characterize DARG interactions and their impact on neuronal viability. This research aims to develop novel therapeutic strategies targeting neurotoxic glia.

Contact details

Professor Stefano Pluchino - spp24@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD