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首页> 外文期刊>Cellular Signalling >Chronic WNT/beta-catenin signaling induces cellular senescence in lung epithelial cells
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Chronic WNT/beta-catenin signaling induces cellular senescence in lung epithelial cells

机译：慢性WNT /β-连环蛋白信号传导在肺上皮细胞中诱导细胞衰老

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The rapid expansion of the elderly population has led to the recent epidemic of age-related diseases, including increased incidence and mortality of chronic lung diseases, such as Idiopathic Pulmonary Fibrosis (IPF). Cellular senescence is a major hallmark of aging and has a higher occurrence in IPF. The lung epithelium represents a major site of tissue injury, cellular senescence and aberrant activity of developmental pathways such as the WNT/beta-catenin pathway in IPF. The potential impact of WNT/beta-catenin signaling on alveolar epithelial senescence in general as well as in IPF, however, remains elusive. Here, we characterized alveolar epithelial cells of aged mice and assessed the contribution of chronic WNT/beta-catenin signaling on alveolar epithelial type (AT) II cell senescence. Whole lungs from old (16-24 months) versus young (3 months) mice had relatively less epithelial (EpCAM(+)) but more inflammatory (CD45(+)) cells, as assessed by flow cytometry. Compared to young ATII cells, old ATII cells showed decreased expression of the ATII cell marker Surfactant Protein C along with increased expression of the ATI cell marker Hopx, accompanied by increased WNT/beta-catenin activity. Notably, when placed in an organoid assay, old ATII cells exhibited decreased progenitor cell potential. Chronic canonical WNT/beta-catenin activation for up to 7 days in primary ATII cells as well as alveolar epithelial cell lines induced a robust cellular senescence, whereas the non-canonical ligand WNT5A was not able to induce cellular senescence. Moreover, chronic WNT3A treatment of precision-cut lung slices (PCLS) further confirmed ATII cell senescence. Simultaneously, chronic but not acute WNT/beta-catenin activation induced a profibrotic state with increased expression of the impaired ATII cell marker Keratin 8. These results suggest that chronic WNT/beta-catenin activity in the IPF lung contributes to increased ATII cell senescence and reprogramming. In the fibrotic environment, WNT/beta-catenin signaling thus might lead to further progenitor cell dysfunction and impaired lung repair.
机译：老年人的快速扩张导致了最近的年龄相关疾病的疫情，包括增加慢性肺病的发病率和死亡率，如特发性肺纤维化（IPF）。细胞衰老是衰老的主要标志，并且IPF发生较高。肺上皮代表了IPF中的WNT /β-连环蛋白途径的组织损伤，细胞衰老和异常活性的主要部位。然而，WNT /β-catenin信号传导在肺泡上皮衰老上的潜在影响以及IPF仍然难以捉摸。这里，我们表征了老年小鼠的肺泡上皮细胞，并评估了慢性Wnt /β-连环蛋白信号传导对肺泡上皮型（AT）II细胞衰老的贡献。来自旧（16-24个月）的整肺（16-24个月）与年轻（3个月）小鼠具有相对较少的上皮（EPCAM（+）），但更多的炎症（CD45（+））细胞，如流式细胞术评估。与杨艾生细胞相比，旧的ATII细胞显示ATII细胞标记表面活性剂蛋白C的表达降低以及ATI细胞标志物HOPX的增加，伴随着增加的Wnt /β-连环蛋白活性。值得注意的是，当放置在有机素测定中时，旧的ATII细胞表现出祖细胞势下降。慢性典型WNT /β-catenin活化在原发性ATII细胞中最多7天，并且肺泡上皮细胞系诱导稳健的细胞衰老，而非规范配体Wnt5a不能诱导细胞衰老。此外，慢性WNT3A治疗精密切割肺切片（PCLS）进一步证实了ATII细胞衰老。同时，慢性但不是急性Wnt /β-连环蛋白激活诱导了患有ATII细胞标志物角蛋白8的增加表达的突触态。这些结果表明IPF肺中的慢性WNT /β-连环蛋白活性有助于增加ATII细胞衰老重新编程。在纤维化环境中，WNT /β-连环蛋白信号传导可能导致祖细胞功能障碍和肺部修复受损。

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