Wnt/β-catenin signaling is critical for regenerative potential of distal lung epithelial progenitor cells in homeostasis and emphysema,STEM CELLS

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Wnt/β-catenin signaling is critical for regenerative potential of distal lung epithelial progenitor cells in homeostasis and emphysema
STEM CELLS ( IF 4.0 ) Pub Date : 2020-06-18 , DOI: 10.1002/stem.3241
Yan Hu ₁ , John-Poul Ng-Blichfeldt _{2,

3} , Chiharu Ota ₂ , Chiara Ciminieri _{1,

4} , Wenhua Ren ₁ , Pieter S Hiemstra ₅ , Jan Stolk ₅ , Reinoud Gosens ₄ , Melanie Königshoff _{1,

2}

Affiliation

Wnt/β‐catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/β‐catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/β‐catenin responsive progenitor cells and the potential impact of Wnt/β‐catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/β‐catenin signaling in lung organoid formation. We identified an organoid‐forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/β‐catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/β‐catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wntlow epithelial progenitors. Further ectopic Wnt/β‐catenin activation specifically led to an increase in alveolar organoid number; however, the subsequent proliferation of alveolar epithelial cells in the organoids did not require constitutive Wnt/β‐catenin signaling. Distal lung epithelial progenitor cells derived from the mouse model of elastase‐induced emphysema exhibited reduced organoid forming capacity. This was rescued by Wnt/β‐catenin signal activation, which largely increased the number of alveolar organoids. Together, our study reveals a novel mechanism of lung epithelial progenitor cell activation in homeostasis and emphysema.

中文翻译：

Wnt/β-连环蛋白信号对远端肺上皮祖细胞在稳态和肺气肿中的再生潜力至关重要

Wnt/β-连环蛋白信号在肺发育和各种成人组织中调节祖细胞命运决定。Wnt/β-连环蛋白信号的异位激活促进肺气肿的组织修复，肺气肿是一种破坏性肺病，肺实质组织进行性丧失。Wnt/β-catenin 响应祖细胞的特性以及 Wnt/β-catenin 信号传导对肺气肿中成人远端肺上皮祖细胞功能的潜在影响知之甚少。在这里，我们使用 TCF/Lef:H2B/GFP 报告小鼠来研究 Wnt/β-catenin 信号在肺类器官形成中的作用。我们鉴定了一种形成类器官的成人远端肺上皮祖细胞群，其特征是 Wnt/β-catenin 活性低，富含俱乐部和肺泡上皮类型 (AT)II 细胞。源自 Wntlow 上皮祖细胞的远端肺类器官的多种亚型的启动需要内源性 Wnt/β-连环蛋白活性。进一步的异位 Wnt/β-catenin 激活特异性地导致肺泡类器官数量的增加；然而，随后类器官中肺泡上皮细胞的增殖不需要组成型 Wnt/β-catenin 信号传导。来自弹性蛋白酶诱导的肺气肿小鼠模型的远端肺上皮祖细胞表现出降低的类器官形成能力。这被 Wnt/β-catenin 信号激活所挽救，这大大增加了肺泡类器官的数量。总之，我们的研究揭示了肺上皮祖细胞在体内平衡和肺气肿中活化的新机制。

更新日期：2020-06-18

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