Laboratory of Pharmacology, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy.
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy.
Int J Mol Sci. 2022 Aug 26;23(17):9713. doi: 10.3390/ijms23179713.
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 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 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 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.
皮肤损伤是结节性硬化症（TSC）的特征之一，这是一种遗传性疾病，由于 hamartin 或 tuberin 的缺失，mTOR 过度激活。迄今为止，需要针对 TSC 皮肤损伤的新型药理学治疗方法，因为这些损伤虽然是良性的，但仍然会影响患者的生活，因为手术或雷帕霉素给药都不能防止其复发。在这里，我们证明了由于表观遗传事件而不表达 tuberin 的原发性 TSC2 细胞在皮下注射到裸鼠中时会导致皮肤损伤和毛囊新生。tuberin 缺失的细胞定位于毛球和成熟毛发旁边，其中 S6 和 Erk 的高磷酸化表明 mTOR 过度激活。有趣的是，5-氮杂胞苷处理减少了毛囊，表明组蛋白修饰剂可能对因表观遗传事件而缺乏 tuberin 的 TSC 病变有效。此外，我们证明了原发性 TSC2 细胞具有转移能力：当皮下注射时，它们到达血液和淋巴系统并侵袭肺部，导致肺泡壁增大。TSC2 细胞在体内生存和迁移的能力使我们的小鼠模型非常适合实时跟踪疾病的进展并测试潜在的药物治疗方法。
