1. IL-4-induced SOX9 confers lineage plasticity to aged adult lung stem cells.
- Author
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Cai XT, Jia M, Heigl T, Shamir ER, Wong AK, Hall BM, Arlantico A, Hung J, Menon HG, Darmanis S, Brightbill HD, Garfield DA, and Rock JR
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Adult Stem Cells metabolism, Alveolar Epithelial Cells metabolism, Alveolar Epithelial Cells drug effects, Aging metabolism, Cell Differentiation, Signal Transduction, Humans, Macrophages metabolism, Interleukin-4 metabolism, SOX9 Transcription Factor metabolism, SOX9 Transcription Factor genetics, Bleomycin, Cell Lineage, Lung metabolism, Lung pathology
- Abstract
Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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