A Cell Interactome Approach to Model, Characterise and understand Novel Mechanisms of Disease in Progressive Multiple Sclerosis

(co-supervised with A Nicaise and I Mohorianou)

Recent work suggests that cellular ageing, known as senescence, of endogenous stem-like cells in the brain may contribute to the chronic inflammation and neurodegeneration seen in people with progressive multiple sclerosis (PMS). Using an inducible system, that directly reprograms human fibroblasts into induced neural stem cells (iNSCs), we have generated patient PMS iNSC lines, which display a pro-inflammatory senescent phenotype that is transferred horizontally to non-senescent cells. Towards studying how these cells can communicate with neighbouring cells within a complex environment, we have developed a hybrid brain organoid system where developmentally mature brain organoids are cut at the air liquid interface (ALICOs) and iNSCs are transplanted and integrate within the tissue.

This project aims at providing new insights into the function and impact of disease-associated iNSCs on cerebral organoids, potentially promoting/inducing (i) chronic inflammation and senescence, (ii) impairing the longevity of the ALICO, and (iii) mimicking the neurodegeneration and brain atrophy seen in PMS patients.

We have developed a novel RABID sequencing-based approach, where the interactome between exogenous and endogenous cells within the hybrid ALICO system is analysed via the use of rabies virus barcodes and downstream single cell sequencing. Techniques will consist of generation of viruses and viral transductions, cell culture, organoid culture, FACS, single cell sequencing, data analysis and interpretation. Combining human based disease modelling, organoids, and state of the art interactome analysis this project aims to uncover new mechanisms by which PMS stem cells contribute to ongoing inflammation and neurodegeneration.