Airway epithelial cell differentiation relies on deficient Hedgehog signalling in COPD
Airway epithelial cell differentiation relies on deficient Hedgehog signalling in COPD
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DOI：
10.1016/j.ebiom.2019.11.033
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发表时间：
2020-01-01
期刊：
影响因子：
11.1
通讯作者：
Dormoy, Valerian
中科院分区：
文献类型：
--
作者：
Belgacemi, Randa;Luczka, Emilie;Dormoy, Valerian
背景：Hedgehog（HH）通路在器官发育的背景下不断受到审查。肺形态发生需要HH信号传导，HH信号传导随后通过调节上皮细胞静止和修复来参与肺内稳态。由于上皮重塑是慢性阻塞性肺疾病（COPD）的一个标志，我们调查是否HH途径的主要分子演员参与气道上皮细胞分化，我们分析了他们在COPD patient.Methods：在气道上皮细胞（AEC）的气液界面培养上清液中的声音HH（Shh）分泌的变化。通过RT-qPCR、蛋白质印迹和免疫染色评价HH途径活化。HH信号传导的抑制在上皮细胞分化期间在Shh螯合后实现。HH通路的核心成分定位进行了调查，在肺组织从非COPD和COPD patients.Findings：我们表明，祖细胞的AEC产生负责HH信号的激活过程中的分化。阻止配体诱导的HH激活导致建立重塑上皮，基底细胞数量增加，纤毛发生减少。Gli 2转录激活因子是调控AEC分化的关键因子。更重要的是，Gli 2和Smo在COPD患者的AEC中丢失。解释：我们的数据表明HH通路对气道上皮细胞分化至关重要，并强调其在COPD相关上皮重塑中的作用。(C)2019年，任作家。由爱思唯尔公司出版
Background: Hedgehog (HH) pathway is constantly under scrutiny in the context of organ development. Lung morphogenesis requires HH signalling which participates thereafter to the pulmonary homeostasis by regulating epithelial cell quiescence and repair. Since epithelial remodelling is a hallmark of Chronic Obstructive Pulmonary Disease (COPD), we investigated whether the main molecular actors of HH pathway participate to airway epithelial cell differentiation and we analysed their alterations in COPD patients.Methods: Sonic HH (Shh) secretion was assessed by ELISA in airway epithelial cell (AEC) air-liquid interface culture supernatants. HH pathway activation was evaluated by RT-qPCR, western blot and immunostaining. Inhibition of HH signalling was achieved upon Shh chelation during epithelial cell differentiation. HH pathway core components localization was investigated in lung tissues from non-COPD and COPD patients.Findings: We demonstrate that progenitors of AEC produced Shh responsible for the activation of HH signalling during the process of differentiation. Preventing the ligand-induced HH activation led to the establishment of a remodelled epithelium with increased number of basal cells and reduced ciliogenesis. Gli2 activating transcription factor was demonstrated as a key-element in the regulation of AEC differentiation. More importantly, Gli2 and Smo were lost in AEC from COPD patients.Interpretation: Our data suggest that HH pathway is crucial for airway epithelial cell differentiation and highlight its role in COPD-associated epithelial remodelling. (C) 2019 The Authors. Published by Elsevier B.V.