mTOR信号通路在骨髓间充质干细胞移植对肺淋巴管肌瘤病肺损伤干预的调控机制研究

Pulmonary lymphangioleiomyomatosis(P-LAM) is a rare and difficult-to-treat lung disease. It is mainly characterized by diffuse thin-walled cystic changes and nodular proliferation of both lungs. To the best of our knowledge, there are no effective therapies on this disease and few studies focusing on P-LAM pathogenesis existed because of the lack of the animal models of P-LAM. Our preliminary study found Tbx4-rtTA+/Teto-Cre+/Tsc2fx/fx mice developed spontaneous PLAM-like pulmonary injuries with Tsc2 gene loss specific in lung mesenchymal cells, suggesting successful establishment of animal model of P-LAM. Compared to healthy wide-type control, lung MSCs in this mouse of strain were found to have restricted abilities of proliferation and migration as well as abnormal differentiation. Our study suggested that bone marrow MSCs possessed the potential of lung differentiation, therefore participating in the process of lung tissue repair. As we know, no studies existed on the treatment of MSCs on P-LAM derived injuries so far. It should be mentioned that mTOR signaling pathway is believed to be involved in the process of intracellular regulation on cell proliferation, growth or apoptosis. Our preliminary study suggested abnormal mTOR signaling might play a role in the generation of dysfunctional L-MSCs in P-LAM. However, the underlying mechanism remains unclear. The current study will investigate the role of mTOR signaling pathway on the treatment of BM-MSCs on P-LAM like injuries, which would strengthen our understanding of LAM pathogenesis and further guide LAM treatment.

肺淋巴管肌瘤病（P-LAM）是一种罕见的肺部疾病，目前无有效治疗方法。因缺乏可靠的LAM动物模型，LAM发病机制研究相对较少。我们发现，Tbx4-rtTA+/Teto-Cre+/Tsc2fx/fx系小鼠肺间充质细胞中Tsc2基因特异性缺失，可出现LAM样肺损伤，经证实为可靠的LAM小鼠模型；与健康对照小鼠比较，该系小鼠肺间充质干细胞（L-MSCs）增殖活跃、迁移能力受抑制、转分化功能异常。我们前期研究提示mTOR信号通路异常可能与LAM中L-MSCs功能异常相关，但具体机制尚不明确。骨髓间充质干细胞（BM-MSCs）具肺向分化潜能和肺部特殊亲和性，可参与肺组织损伤修复。目前国内外尚无MSCs在LAM肺损伤中的相关研究。本研究使用LAM小鼠模型探讨BM-MSCs移植对LAM样肺部病变形成过程及转归的影响，进一步研究mTOR信号通路在LAM发病中的作用机制，为LAM的精准防治提供新的理论基础。

肺淋巴管肌瘤病（LAM）是一种相对罕见、具破坏性和转移性、难治的、低度恶性肿瘤性肺部疾病，主要病理改变为双肺弥漫性薄壁囊性病变和结节样增生，无预防措施，治疗方法有限，病程难以逆转。因缺乏自发的、可靠的LAM动物模型和新鲜组织标本，关于LAM发病机制、病理生理的基础研究相对较少。目前间充质干细胞（MSC）功能异常在LAM样肺病变中是否存在作用，国内外仍未见相关报道。在第一部分研究中，我们顺利的发现Tbx4-rtTA+/Teto-Cre+/Tsc2fx/fx系小鼠肺间充质细胞中Tsc2基因特异性缺失，可自发出现LAM样肺病变，经病理证实为可靠的LAM小鼠模型。第二部分研究中，与健康对照小鼠比较，LAM模型小鼠肺间充质干细胞（L-MSCs）增殖活跃、迁移能力受抑制、干细胞转分化功能异常、mTOR信号通路异常，这一发现与我们课题组所观察到的LAM患者L-MSCs细胞功能差异相符；然而，两组小鼠骨髓间充质干细胞（BM-MSCs）细胞功能无明显差异。此外，通过LAM差异基因表达谱生物信息学分析发现mTOR信号通路异常仍是主要因素之一。以上结果提示，LAM样肺病变与L-MSCs细胞功能异常可能相关，这有望为进一步理解LAM发病机制及其预防治疗提供更多线索。第三部分研究中，观察到小鼠BM-MSCs体外培养中可诱导分化，目前仍在进一步摸索小鼠BM-MSCs移植的最佳方案与移植后LAM模型小鼠肺部病理改变的相关性。