Modeling TSC and LAM Using Patient Derived Induced Pluripotent Stem Cells

Abstract : Tuberous sclerosis complex (TSC) is a multi-organ genetic disorder with an estimated incidence of one in 6,000 live births due to mutations in either TSC1 or TSC2. About 30 of women with TSC have lymphangioleiomyomatosis (LAM), a progressive lung disease characterized by abnormal proliferation of smooth muscle-like cells throughout the lungs, leading to lung destruction and eventual respiratory failure. The cause of the tumor development in various tissues is not well understood, in part due to a lack of human TSC1 or TSC2 deficient human cells to study the biology of the disease and perform drug screens. We have now made TSC2deficient human cells using patient induced pluripotent stem cells (iPSCs), lentiviral knockdown, and CRISPR/Cas9 genome editing in embryonic stem cells (ESCs). We have characterized the iPSCs extensively and found that they display abnormal cell size, autophagy regulation, metabolic activity, hyperactive mTOR signaling, and differentiation all characteristics of TSC and LAM cells.