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Summary: Tuberous sclerosis complex (TSC) is a rare neurodevelopmental disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes, leading to a hyperactivated mammalian target of rapamycin (mTOR) pathway, and gray and white matter defects in the brain. To study the involvement of neuron-glia interactions in TSC phenotypes, we generated TSC patient induced pluripotent stem cell (iPSC)-derived cortical neuronal and oligodendrocyte (OL) cultures. TSC neuron mono-cultures showed increased network activity, as measured by calcium transients and action potential firing, and increased dendritic branching. However, in co-cultures with OLs, neuronal defects became more apparent, showing cellular hypertrophy and increased axonal density. In addition, TSC neuron-OL co-cultures showed increased OL cell proliferation and decreased OL maturation. Pharmacological intervention with the mTOR regulator rapamycin suppressed these defects. Our patient iPSC-based model, therefore, shows a complex cellular TSC phenotype arising from the interaction of neuronal and glial cells and provides a platform for TSC disease modeling and drug development. : Nadadhur et al. generated TSC disease models using patient iPSCs. While neuron mono-cultures showed an increase in network activity and dendritic branching, only when co-cultured with oligodendrocytes (OLs), hypertrophy and axonal abnormalities were observed. Neuron-OL interactions, modulated by mTOR regulators, support use of mixed cultures for TSC disease modeling and drug development. Keywords: tuberous sclerosis complex, autism, iPSC, co-culture, glia, oligodendrocyte, neuron, in vitro model, neuronal activity, myelin |
