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Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration
Nature Cell Biology ( IF 21.3 ) Pub Date : 2021-09-02 , DOI: 10.1038/s41556-021-00742-6
Jinwook Choi 1 , Yu Jin Jang 2 , Catherine Dabrowska 1, 3 , Elhadi Iich 1 , Kelly V Evans 1, 3 , Helen Hall 4 , Sam M Janes 4 , Benjamin D Simons 1, 5, 6 , Bon-Kyoung Koo 7 , Jonghwan Kim 2, 8, 9 , Joo-Hyeon Lee 1, 3
Affiliation  

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Following damage, interleukin-1β (IL-1β) signalling-dependent modulation of Jag1 and Jag2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives the reprogramming and acquisition of differentiation plasticity. We identify the transcription factor Fosl2 (also known as Fra2) for secretory cell fate conversion to alveolar type 2 cells that retain the distinct genetic and epigenetic signatures of secretory lineages. We also reveal that human secretory cells positive for KDR (also known as FLK-1) display a conserved capacity to generate alveolar type 2 cells via Notch inhibition. Our results demonstrate the functional role of an IL-1β–Notch–Fosl2 axis in the fate decision of secretory cells during injury repair, proposing a potential therapeutic target for human lung alveolar regeneration.



中文翻译:

由 IL-1β 信号协调的 Notch 活性释放通过 Fosl2 赋予气道祖细胞在肺泡再生过程中的分化可塑性

虽然在成体干细胞中获得细胞可塑性对于组织损伤后的快速再生至关重要,但对控制这一过程的潜在机制知之甚少。我们的数据揭示了肺泡再生过程中炎症信号对气道祖细胞分化可塑性的协调作用。损伤后, Jag1Jag2的白细胞介素 1β (IL-1β) 信号依赖调制纤毛细胞中的表达导致分泌细胞中Notch信号传导的抑制,从而驱动重编程和获得分化可塑性。我们确定了转录因子 Fosl2(也称为 Fra2),用于将分泌细胞命运转换为保留分泌谱系的独特遗传和表观遗传特征的 2 型肺泡细胞。我们还揭示了对 KDR(也称为 FLK-1)呈阳性的人类分泌细胞显示出通过 Notch 抑制生成 2 型肺泡细胞的保守能力。我们的研究结果证明了 IL-1β-Notch-Fosl2 轴在损伤修复过程中分泌细胞命运决定中的功能作用,提出了人类肺泡再生的潜在治疗靶点。

更新日期:2021-09-02
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