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Release of Notch activity coordinated by IL-1 beta signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration

Choi, J; Jang, YJ; Dabrowska, C; Iich, E; Evans, K; Hall, H; Janes, SM; ... Lee, J-H; + view all (2021) Release of Notch activity coordinated by IL-1 beta signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration. Nature Cell Biology , 23 pp. 953-966. 10.1038/s41556-021-00742-6. Green open access

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Abstract

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.

Type: Article
Title: Release of Notch activity coordinated by IL-1 beta signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41556-021-00742-6
Publisher version: https://doi.org/10.1038/s41556-021-00742-6
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, IN-VITRO EXPANSION, STEM-CELLS, EPITHELIAL PROGENITORS, RECEPTOR NR4A2, LUNG, REPAIR, MAINTENANCE, MECHANISMS, CONTRIBUTE, RESPONSES
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10135279
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