Kim Sally Yunsun, McTeague David, Cheong Sek-Shir, Hind Matthew, Dean Charlotte H
National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
Front Cell Dev Biol. 2024 Feb 27;12:1349312. doi: 10.3389/fcell.2024.1349312. eCollection 2024.
Many adult lung diseases involve dysregulated lung repair. Deciphering the molecular and cellular mechanisms that govern intrinsic lung repair is essential to develop new treatments to repair/regenerate the lungs. Aberrant Wnt signalling is associated with lung diseases including emphysema, idiopathic pulmonary fibrosis and pulmonary arterial hypertension but how Wnt signalling contributes to these diseases is still unclear. There are several alternative pathways that can be stimulated upon Wnt ligand binding, one of these is the Planar Cell Polarity (PCP) pathway which induces actin cytoskeleton remodelling. Wnt5a is known to stimulate the PCP pathway and this ligand is of particular interest in regenerative lung biology because of its association with lung diseases and its role in the alveolar stem cell niche. To decipher the cellular mechanisms through which Wnt5a and the PCP pathway affect alveolar repair we utilised a 3-D model of lung injury and repair, the AIR model. Our results show that Wnt5a specifically enhances the alveolar epithelial progenitor cell population following injury and surprisingly, this function is attenuated but not abolished in mouse lungs in which the PCP pathway is dysfunctional. However, tracheal epithelial cells show reduced stiffness and alveolar epithelial cells are less migratory than wildtype (WT), indicating that lung epithelial cells have a reduced capacity for repair. These findings provide important mechanistic insight into how Wnt5a and the PCP pathway contribute to lung repair and indicate that these components of Wnt signalling may be viable targets for the development of pro-repair treatments.
许多成人肺部疾病都涉及肺修复失调。解读控制肺固有修复的分子和细胞机制对于开发修复/再生肺的新疗法至关重要。异常的Wnt信号通路与包括肺气肿、特发性肺纤维化和肺动脉高压在内的肺部疾病相关，但Wnt信号通路如何导致这些疾病仍不清楚。Wnt配体结合后可激活几种替代途径，其中之一是平面细胞极性（PCP）途径，它可诱导肌动蛋白细胞骨架重塑。已知Wnt5a可激活PCP途径，由于其与肺部疾病的关联及其在肺泡干细胞微环境中的作用，这种配体在再生肺生物学中特别受关注。为了解读Wnt5a和PCP途径影响肺泡修复的细胞机制，我们利用了肺损伤和修复的三维模型——AIR模型。我们的结果表明，Wnt5a在损伤后特异性地增强了肺泡上皮祖细胞群体，令人惊讶的是，在PCP途径功能失调的小鼠肺中，这种功能减弱但并未消除。然而，气管上皮细胞的硬度降低，肺泡上皮细胞的迁移能力低于野生型（WT），这表明肺上皮细胞的修复能力降低。这些发现为Wnt5a和PCP途径如何促进肺修复提供了重要的机制见解，并表明Wnt信号通路的这些成分可能是开发促进修复疗法的可行靶点。
