Single nuclei transcriptomics reveals cellular diversity in TSC subependymal giant cell astrocytomas

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by benign growths called hamartomas that are a significant cause of morbidity and mortality. Hamartomas are found along the neurocutaneous axis including along the brain's ventricles near the boundaries of the striatum. They can be categorized by size and include small subependymal nodules (SENs) or larger subependymal giant cell astrocytomas (SEGAs). Here, we describe a quantitative analysis of SEGA cell identities based on single nuclei RNA sequencing. SEGAs contain several cell types. In contrast to unaffected samples, SEGAs have pronounced vasculature, more endothelial cells, increased perivascular macrophages, less myelination, and altered immature oligodendrocyte progenitor cells. Furthermore, at least 40% of SEGA cells are related to GABAergic neurons. We identified cell-type-specific changes in gene expression patterns and a subset of transcripts that indicate altered neuronal excitation. These results reveal the complex cellular niche of SEGAs and opportunities and challenges for advancing treatments.