Journal
STEM CELL REPORTS
Volume 12, Issue 1, Pages 42-56Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2018.11.019
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Funding
- Amsterdam Neuroscience
- EU MSCA-ITN CognitionNet [FP7-PEOPLE-2013-ITN 607508]
- DEFINE, a Wellcome Trust Strategic Award [100202]
- ZonMw VIDI Research grant [91712343]
- E-Rare Joint Call project [9003037601]
- European Leukodystrophy Association (ELA) Research Grant [2014-012L1]
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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.
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