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Stem Cell Reports. 2019 Jan 8;12(1):42-56. doi: 10.1016/j.stemcr.2018.11.019. Epub 2018 Dec 20.

Neuron-Glia Interactions Increase Neuronal Phenotypes in Tuberous Sclerosis Complex Patient iPSC-Derived Models.

Author information

1
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, the Netherlands.
2
Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
3
Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, the Netherlands.
4
Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, the Netherlands; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, the Netherlands. Electronic address: vm.heine@vumc.nl.

Abstract

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.

KEYWORDS:

autism; co-culture; glia; iPSC; in vitro model; myelin; neuron; neuronal activity; oligodendrocyte; tuberous sclerosis complex

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