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OBJECTIVE: Assess if cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with multiple sclerosis (MS) can bring a better understanding of genetic contribution of MS pathogenesis.
BACKGROUND: Multiple sclerosis is an auto-immune disease characterized by inflammation, demyelination and neural degeneration. It is now accepted that MS development is influenced by both genetic and environmental factors. iPSCs retain genomic information from the original patient. Cerebral organoids can be derived from patient iPSCs creating an innovative tool to study neurodegenerative disorder pathogenesis, such as multiple sclerosis, with strict control of the microenvironment.
DESIGN/METHODS: Cerebral organoids were derived from iPSCs 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 in vitro.
RESULTS:First analysis of the stem cell population showed a significant lower expression of stem cell marker SOX2 in MS organoids compared to control. Stem cell proliferation capacity was assessed by Ki67 marker analysis. It revealed a significant lower Ki67 expression in MS organoids, particularly PPMS, compared to control. We then verified if stem cell differentiation capacity was also disrupted by analyzing mature neuron markers CTIP2 and TBR1 as well as oligodendrocyte marker Olig2. A significant increase of both neuronal markers was detected in PPMS organoids compared to control while a strong decrease of Olig2 expression was detected in MS organoids. Cell cycle inhibitor p21 immunostainings showed a significant reduction of p21 expression in MS samples, particularly in PPMS, suggesting that stem cell proliferation/differentiation dysregulation might be led by p21 pathway independently of the p53 mediated apoptosis pathway.
CONCLUSIONS:This new genetic model of MS highlighted a disruption of the cell cycle mediated by p21, leading to a disruption of the proliferation/differentiation capacity of neural progenitors in MS samples, particularly PPMS.