An injury-induced mesenchymal-epithelial cell niche coordinates regenerative responses in the lung

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-12-13 DOI:10.1126/science.ado5561

Dakota L. Jones, Michael P. Morley, Xinyuan Li, Yun Ying, Gan Zhao, Sarah E. Schaefer, Luis R. Rodriguez, Fabian L. Cardenas-Diaz, Shanru Li, Su Zhou, Ullas V. Chembazhi, Mijeong Kim, Chen Shen, Ana Nottingham, Susan M. Lin, Edward Cantu, Joshua M. Diamond, Maria C. Basil, Andrew E. Vaughan, Edward E. Morrisey

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Abstract

Severe lung injury causes airway basal stem cells to migrate and outcompete alveolar stem cells, resulting in dysplastic repair. We found that this “stem cell collision” generates an injury-induced tissue niche containing keratin 5⁺ epithelial cells and plastic Pdgfra⁺ mesenchymal cells. Single-cell analysis revealed that the injury-induced niche is governed by mesenchymal proliferation and Notch signaling, which suppressed Wnt/Fgf signaling in the injured niche. Conversely, loss of Notch signaling rewired alveolar signaling patterns to promote functional regeneration and gas exchange. Signaling patterns in injury-induced niches can differentiate fibrotic from degenerative human lung diseases through altering the direction of Wnt/Fgf signaling. Thus, we have identified an injury-induced niche in the lung with the ability to discriminate human lung disease phenotypes.

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损伤诱导的间充质上皮细胞生态位协调肺的再生反应。

严重的肺损伤导致气道基底干细胞迁移并胜过肺泡干细胞，导致发育不良修复。我们发现这种“干细胞碰撞”产生了一个包含角蛋白5+上皮细胞和可塑Pdgfra+间充质细胞的损伤诱导的组织生态位。单细胞分析表明，损伤诱导的生态位受间充质增殖和Notch信号的调控，Notch信号抑制了损伤生态位中的Wnt/Fgf信号。相反，Notch信号的缺失会重新连接肺泡信号模式，从而促进功能再生和气体交换。损伤诱导小生境中的信号模式可以通过改变Wnt/Fgf信号传导方向来区分纤维化和退行性人肺疾病。因此，我们已经确定了肺中具有区分人类肺部疾病表型能力的损伤诱导的生态位。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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