Modeling tuberous sclerosis complex with human induced pluripotent stem cells.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with a birth incidence of 1:6000 in the United States that is characterized by the growth of non-cancerous tumors in multiple organ systems including the brain, kidneys, lungs, and skin. Importantly, TSC is also associated with significant neurological manifestations including epilepsy, TSC-associated neuropsychiatric disorders, intellectual disabilities, and autism spectrum disorder. Mutations in the TSC1 or TSC2 genes are well-established causes of TSC, which lead to TSC1/TSC2 deficiency in organs and hyper-activation of the mammalian target of rapamycin signaling pathway. Animal models have been widely used to study the effect of TSC1/2 genes on the development and function of the brain. Despite considerable progress in understanding the molecular mechanisms underlying TSC in animal models, a human-specific model is urgently needed to investigate the effects of TSC1/2 mutations that are unique to human neurodevelopment.

Data sources: Literature reviews and research articles were published in PubMed-indexed journals.

Results: Human-induced pluripotent stem cells (iPSCs), which capture risk alleles that are identical to their donors and have the capacity to differentiate into virtually any cell type in the human body, pave the way for the empirical study of previously inaccessible biological systems such as the developing human brain.

Conclusions: In this review, we present an overview of the recent progress in modeling TSC with human iPSC models, the existing limitations, and potential directions for future research.