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OBJECTIVE: We propose to use patient induced pluripotent stem cell derived cerebral organoids to study the genetic components of multiple sclerosis.
BACKGROUND: Multiple sclerosis is an auto-immune disease characterized by inflammation, demyelination and neural degeneration. MS etiology and genetic determinants are still poorly understood. Recent advances in cerebral organoid cultures provide new avenues to investigate human disorders. Cerebral organoids contain ventricular structures aligned by neural stem cells, progenitor cells in various stages of differentiation, and neurons. Moreover, the lack of blood vessels and immune cells in organoids allows the study of the effect of MS genetic component alone on neural cells.
DESIGN: Cerebral organoids were derived from iPS cells of patients with MS. We analyzed stem cell proliferation, migration and differentiation in neuronal and glial lineages in MS organoids compared to healthy control organoids after 42 days of growth in vitro.
RESULTS: MS cerebral organoids seemed to grow faster compared to control organoids, associated with thicker cortical structures, suggesting dysregulation of the stem cell proliferation/differentiation capacity. Immunostainings showed a significant reduction of the cyclin-dependent kinase inhibitor p21 expression in MS samples, particularly in PPMS. Loss of p21 seems to induce a slight decrease of stem cell marker SOX2 as well as a significant increase of neuronal marker CTIP2 in MS samples, while no significant difference was observed for TBR2-positive intermediate progenitors. A further analysis of DNA damage and senescence/apoptosis markers in neural population is currently being performed.
CONCLUSIONS: Cerebral organoids seem to be a viable human model to study the pathology MS using stem cells derived from patient. This new model allows the study of patient-specific genetic background as an inner trigger of MS and will help to identify potential target for therapeutic strategies designed to promote myelin repair in MS.