Hippo signaling cooperates with p53 to regulate lung airway mucous cell metaplasia.

IF 4 3区 医学 Q2 CELL BIOLOGY
Jiangying Liu, Dan Luo, Haidi Huang, Rongzi Mu, Jianghong Yuan, Ming Jiang, Chuwen Lin, Honggang Xiang, Xinhua Lin, Haihan Song, Yongchun Zhang
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引用次数: 0

Abstract

Airway mucous cell metaplasia is a significant feature of many chronic airway diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma. However, the mechanisms underlying this process remain poorly understood. Here, we employ in vivo mouse genetic models to demonstrate that Hippo and p53 cooperate to modulate the differentiation of club cells into goblet cells. We reveal that ablation of Mst1 and Mst1 (Mst1/2), the core components of Hippo signaling, significantly reduces mucous metaplasia in the lung airways in a lipopolysaccharide (LPS)-induced lung inflammation murine model while promoting club cell proliferation in a Yap-dependent manner. Additionally, we show that deleting Mst1/2 is sufficient to suppress p53 deficiency-mediated goblet cell metaplasia. Finally, single-cell RNA analysis reveals a downregulation of Yap and p53 signaling in goblet cells in the human airways. These findings underscore the important role of Hippo and p53 signaling in regulating airway mucous metaplasia.

Hippo信号与p53合作调控肺气道粘液细胞增生。
气道粘液细胞增生是许多慢性气道疾病(如慢性阻塞性肺病(COPD)、囊性纤维化和哮喘)的一个重要特征。然而,人们对这一过程的机制仍然知之甚少。在这里,我们利用体内小鼠遗传模型证明,Hippo 和 p53 相互合作,调节俱乐部细胞向腺泡细胞的分化。我们发现,在脂多糖(LPS)诱导的肺部炎症小鼠模型中,消减 Hippo 信号转导的核心成分 Mst1 和 Mst1(Mst1/2)可显著减少肺部呼吸道的粘液变性,同时以 Yap 依赖性方式促进俱乐部细胞增殖。此外,我们还发现,删除 Mst1/2 足以抑制 p53 缺乏介导的小腺细胞增生。最后,单细胞 RNA 分析表明,人体气道中的上睑球细胞的 Yap 和 p53 信号下调。这些发现强调了 Hippo 和 p53 信号在调节气道粘液变性中的重要作用。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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