Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration.
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Cell stem cell
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Choi, J., Park, J., Tsagkogeorga, G., Yanagita, M., Koo, B., Han, N., & Lee, J. (2020). Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration.. Cell stem cell, 27 (3), 366-382.e7. https://doi.org/10.1016/j.stem.2020.06.020
Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, Damage-Associated Transient Progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this step-wise mapping to cell fate transitions shows how an inflammatory niche impairs alveolar regeneration by controlling stem cell fate and behavior.
Lung, Stem Cells, Signal Transduction, Cell Differentiation, Alveolar Epithelial Cells
We would like to thank Emma Rawlins (University of Cambridge, UK) for valuable scientific discussions and sharing the mouse lines; We would like to thank Randall Johnson (University of Cambridge, UK) for sharing Hif1aflox/flox mouse line; Nisha Narayan and Brian Huntly for sharing materials and discussion on glycolysis experiments; Irina Pshenichnaya (Histology), Maike Paramor (NGS library), Peter Humphreys (Imaging), Andy Riddell (Flow cytometry), Simon McCallum (Flow cytometry, Cambridge NIHR BRC Cell Phenotyping Hub), Katarzyna Kania (single cell sequencing at Cancer Research UK), and Cambridge Stem Cell Institute core facilities for technical assistance; Papworth Hospital Research Tissue Bank for providing tissue samples from IPF and lung adenocarcinoma (T02233); Kelly Evans for sharing histology samples of human lung tissue samples; Seungmin Han and Woochang Hwang for discussion on the scRNA-seq analysis; Life Science Editors for editorial assistance; All Lee Lab members for helpful discussion. This work was supported by Wellcome and the Royal Society (107633/Z/15/Z) and European Research Council Starting Grant (679411). J.C. was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A3A03005399).
WELLCOME TRUST (107633/Z/15/Z)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (679411)
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External DOI: https://doi.org/10.1016/j.stem.2020.06.020
This record's URL: https://www.repository.cam.ac.uk/handle/1810/307201
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Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/