Impact of TSC2-deficient neural cells on microglial structure and function in an induced human pluripotent stem cell model of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare genetic disease caused by mutations in the TSC2 gene. The TSC brain develops malformed tissue clusters called cortical tubers (CTs), which cause epilepsy and cognitive problems. CTs result from abnormal cell differentiation, where clusters of enlarged neural stem cells, astroglia, and hyperactive neurons form. CTs notably present markers of cell stress and inflammation, which are known to affect organelles, cell differentiation, and neuron function in CTs. CTs are surrounded by microglia, the resident immune cell of the brain, required for proper brain function and the main drivers of inflammation. Though known to be a feature of TSC brain lesions, the role of microglia in CT formation is completely unknown. Therefore, I will investigate if microglia contribute to CT formation and, study for the first time, how the interaction with TSC2 mutant cells affect microglial function. Using advanced molecular and imaging techniques, I will study if microglia affect CT formation in a co-culture model of human pluripotent stem cell-derived microglia and TSC2 mutant neural cells. Our results will finally elucidate the role of microglia in CTs, a critical advance to uncover novel treatments for TSC.