Wnt/β-catenin signaling is critical for regenerative potential of distal lung epithelial progenitor cells in homeostasis and emphysema
Wnt/β-catenin signaling is critical for regenerative potential of distal lung epithelial progenitor cells in homeostasis and emphysema
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Wnt/β-Catenin信号通路在肺远端上皮祖细胞内稳和肺气肿的再生潜能中起关键作用
DOI：
10.1002/stem.3241
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发表时间：
2020-06-18
期刊：
影响因子：
5.2
通讯作者：
Koenigshoff, Melanie
中科院分区：
文献类型：
--
作者：
Hu, Yan;Ng-Blichfeldt, John-Poul;Koenigshoff, Melanie
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，肺气肿是一种毁灭性的肺部疾病，伴有肺实质组织的进行性损失。Wnt/ β -连环蛋白应答祖细胞的特性以及Wnt/ β -连环蛋白信号传导对肺气肿成人远端肺上皮祖细胞功能的潜在影响尚不清楚。在这里，我们使用TCF/ left:H2B/GFP报告小鼠来研究Wnt/ β -连环蛋白信号在肺类器官形成中的作用。我们发现了一个类器官形成的成人远端肺上皮祖细胞群，其特征是Wnt/ β -连环蛋白活性低，在俱乐部和肺泡上皮型（AT）II细胞中富集。内源性Wnt/ β -连环蛋白活性对于源自Wnt（低）上皮祖细胞的远端肺类器官的多种亚型的起始是必需的。进一步的异位Wnt/ β -连环蛋白激活特异性地导致肺泡类器官数量的增加；然而，类器官中随后的肺泡上皮细胞增殖不需要组成型Wnt/ β -连环蛋白信号。来自弹性酶诱导肺气肿小鼠模型的远端肺上皮祖细胞显示出类器官形成能力降低。这是由Wnt/ β -连环蛋白信号激活挽救的，这在很大程度上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激活在体内平衡和肺气肿中的新机制。
Wnt/beta-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/beta-catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/beta-catenin responsive progenitor cells and the potential impact of Wnt/beta-catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used a TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/beta-catenin signaling in lung organoid formation. We identified an organoid-forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/beta-catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/beta-catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wnt(low)epithelial progenitors. Further ectopic Wnt/beta-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/beta-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/beta-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.