An injury-induced tissue niche shaped by mesenchymal plasticity coordinates the regenerative and disease response in the lung.
An injury-induced tissue niche shaped by mesenchymal plasticity coordinates the regenerative and disease response in the lung.
复制标题
由间充质可塑性形成的损伤诱导的组织生态位协调肺部的再生和疾病反应。
DOI：
10.1101/2024.02.26.582147
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Morrisey,E
中科院分区：
文献类型：
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作者：
Jones,DakotaL;Morley,MichaelP;Li,Xinyuan;Ying,Yun;Cardenas-Diaz,FabianL;Li,Shanru;Zhou,Su;Schaefer,SarahE;Chembazhi,UllasV;Nottingham,Ana;Lin,Susan;Cantu,Edward;Diamond,JoshuaM;Basil,MariaC;Vaughan,AndrewE;Morrisey,E
严重的肺损伤会导致基底干细胞迁移并在竞争中击败肺泡干细胞，从而导致发育不良修复和气体交换功能丧失。这种“干细胞碰撞”是多步骤过程的一部分，现已发现该过程可产生包含角蛋白 5+ 上皮细胞和塑料 Pdgfra+ 间充质细胞的损伤诱导组织生态位 (iTCH)。时间和空间单细胞分析表明，iTCH 受间充质增殖和 Notch 信号传导控制，Notch 信号传导抑制 iTCH 中的 Wnt 和 Fgf 信号传导。相反，iTCH 中 Notch 的缺失会重新连接肺泡信号传导模式，以促进肿瘤再生和气体交换。 iTCH 的信号传导模式可以通过 FGF 和 WNT 信号传导的并置流动来区分纤维化和退行性人类肺部疾病的表型。这些数据揭示了肺部与 iTCH 相关的损伤和疾病的出现，以及使用 iTCH 特定信号传导模式区分人类肺部疾病表型的能力。
Severe lung injury causes basal stem cells to migrate and outcompete alveolar stem cells resulting in dysplastic repair and a loss of gas exchange function. This “stem cell collision” is part of a multistep process that is now revealed to generate an injury-induced tissue niche (iTCH) containing Keratin 5+ epithelial cells and plastic Pdgfra+ mesenchymal cells. Temporal and spatial single cell analysis reveals that iTCHs are governed by mesenchymal proliferation and Notch signaling, which suppresses Wnt and Fgf signaling in iTCHs. Conversely, loss of Notch in iTCHs rewires alveolar signaling patterns to promote euplastic regeneration and gas exchange. The signaling patterns of iTCHs can differentially phenotype fibrotic from degenerative human lung diseases, through apposing flows of FGF and WNT signaling. These data reveal the emergence of an injury and disease associated iTCH in the lung and the ability of using iTCH specific signaling patterns to discriminate human lung disease phenotypes.