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Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model
Clara Bernardelli1, Eloisa Chiaramonte1, Silvia Ancona1
1Laboratory of Pharmacology, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy.
Abstract:
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.
Insights
Tuberin-deficient cells from tuberous sclerosis complex (TSC) caused skin lesions and metastasis in mice. Chromatin remodeling agents may treat TSC skin lesions by targeting epigenetic changes.
Area of Science:
- Genetics
- Dermatology
- Oncology
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder characterized by hyperactive mTOR signaling due to mutations in TSC1 (hamartin) or TSC2 (tuberin).
- Cutaneous lesions are a common manifestation of TSC, impacting patient quality of life, and current treatments like surgery or rapamycin have limitations due to recurrence.
- There is a need for novel therapeutic strategies targeting the underlying mechanisms of TSC-associated skin lesions.
Purpose of the Study:
- To investigate the role of epigenetically modified TSC2-deficient cells in the development of cutaneous lesions.
- To explore the potential of chromatin remodeling agents as a therapeutic approach for TSC skin manifestations.
- To establish a preclinical mouse model for studying TSC progression and evaluating novel treatments.
Main Methods:
- Subcutaneous injection of primary TSC2-deficient (TSC2-/meth) cells into nude mice to induce cutaneous lesions.
- Histological analysis of lesions to assess cell localization, hair follicle formation, and mTOR pathway activation (S6 and Erk phosphorylation).
- Administration of 5-azacytidine, a chromatin remodeling agent, to evaluate its effect on lesion development and metastatic potential.
Main Results:
- TSC2-/meth cells induced cutaneous lesions and follicular neogenesis in mice, with cells localizing to hair bulbs and exhibiting mTOR hyperactivation.
- 5-azacytidine treatment led to a reduction in hair follicles, suggesting efficacy of chromatin remodeling agents.
- In vivo studies revealed that TSC2-/meth cells possess metastatic capabilities, migrating to the bloodstream and lymphatics and invading the lungs.
Conclusions:
- Epigenetically altered TSC2-deficient cells can recapitulate key features of TSC cutaneous lesions and exhibit metastatic potential.
- Chromatin remodeling agents represent a promising therapeutic avenue for TSC skin lesions arising from epigenetic modifications.
- The developed mouse model provides a valuable platform for in vivo assessment of disease progression and pharmacological interventions in TSC.
