Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model

Cutaneous lesions are one of the hallmarks of tuberous sclerosis complex (TSC), a genetic disease in which mTOR is hyperactivated due to the lack of hamartin or tuberin. To date, novel pharmacological treatments for TSC cutaneous lesions that are benign but still have an impact on a patient's life are needed, because neither surgery nor rapamycin administration prevents their recurrence. Here, we demonstrated that primary TSC2(-/meth) cells that do not express tuberin for an epigenetic event caused cutaneous lesions and follicular neogenesis when they were subcutaneously injected in nude mice. Tuberin-null cells localized in the hair bulbs and alongside mature hairs, where high phosphorylation of S6 and Erk indicated mTOR hyperactivation. Interestingly, 5-azacytidine treatment reduced hair follicles, indicating that chromatin remodeling agents might be effective on TSC lesions in which cells lack tuberin for an epigenetic event. Moreover, we demonstrated that the primary TSC2(-/meth) cells had metastatic capability: when subcutaneously injected, they reached the bloodstream and lymphatics and invaded the lungs, causing the enlargement of the alveolar walls. The capability of TSC2(-/meth) cells to survive and migrate in vivo makes our mouse model ideal to follow the progression of the disease and test potential pharmacological treatments in a time-dependent manner.

Automated summary

Cutaneous lesions are a characteristic feature of tuberous sclerosis complex (TSC), a genetic disease with hyperactivated mTOR signaling. Current treatments for TSC cutaneous lesions lack long-term efficacy, and novel pharmacological approaches are needed. This study demonstrates that chromatin remodeling agents, such as 5-azacytidine, may be effective in treating TSC lesions caused by epigenetic events. Additionally, the study reveals the metastatic capability of TSC cells, providing a valuable mouse model for studying disease progression and testing potential treatments.