ANALYSIS OF DISTINCT CELL POPULATION FATE IN PATIENT-DERIVED CEREBRAL ORGANOID MODEL OF MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an autoimmune neurological disorder characterized by inflammation, demyelination and neural degeneration. However, the origin and evolution of the disease are still poorly understood due to relative inaccessibility of human brain tissue and inadequate animal models to study MS.

Recent advances in 3D cerebral organoid cultures derived from induced pluripotent stem cells (iPSC) provide new avenues to develop models to study cell type- and stage-specific effects of MS. Cerebral organoids contain ventricle-like structures aligned by neural stem cells, progenitor cells in various stages of differentiation and migration, and cortical neurons in a stereotypical inside-out stratified layout. Moreover, it has been previously shown that neurons present in c-organoids were able to get myelinated.

We propose here to develop an innovative model of MS using human cerebral organoids derived from iPS cells of patients with MS. Stem cell proliferation, migration and differentiation in neuronal and glial lineage were assessed in the different type of MS organoids and compared to control organoids after 42 days in vitro.

Upper layers of the cortical structure in PPMS c-organoids were larger compared to control c-organoids, suggesting an imbalance of the stem cell proliferation/differentiation capacity. Immunofluorescence staining for stem cell marker SOX2 revealed that the stem cell pool, localized in the VZ, was significantly reduced in MS organoids compared to control. Additionally, a staining of neuronal markers CTIP2 and TBR1 highlighted an increase of neurogenesis, in PPMS particularly, compared to control. To explain this disturbance of the proliferation/differentiation capacity of the stem cell pool, an analysis of the cleavage plane angle of mitotic cells was performed. A shift from symmetric division towards asymmetric division was revealed in MS compared to control, suggesting an increase of stem cell differentiation and neurogenesis in spite of stem cell proliferation. Further investigations are needed to understand the mechanisms involved.

This study describes an innovative model of MS and will give new insights on the origin and evolution of the disease and will help to identify potential targets for therapeutic strategies in the different types of MS.