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A correctable immune niche for epithelial stem cell reprogramming and post-viral lung diseases
Kangyun Wu, … , Michael E. Hughes, Michael J. Holtzman
Kangyun Wu, … , Michael E. Hughes, Michael J. Holtzman
Published July 25, 2024
Citation Information: J Clin Invest. 2024;134(18):e183092. https://doi.org/10.1172/JCI183092.
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Research Article Pulmonology Article has an altmetric score of 4

A correctable immune niche for epithelial stem cell reprogramming and post-viral lung diseases

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Abstract

Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provided long-lasting correction of reprogramming and broad disease phenotypes. These same control points worked directly in mouse and human basal ESC organoids. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury.

Authors

Kangyun Wu, Yong Zhang, Huiqing Yin-DeClue, Kelly Sun, Dailing Mao, Kuangying Yang, Stephen R. Austin, Erika C. Crouch, Steven L. Brody, Derek E. Byers, Christy M. Hoffmann, Michael E. Hughes, Michael J. Holtzman

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Figure 8

Effect of GPNMB on basal ESC growth and immune activation.

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Effect of GPNMB on basal ESC growth and immune activation.
(A) Protocol ...
(A) Protocol scheme for cell isolation from mouse lungs at 21 days after SeV infection, then FACS for CD31–CD45–EpCAM+Aqp3+ epithelial cells and seeding into 3D organoid culture. (B) Levels of organoid formation from conditions in A and coculture with the indicated immune cell populations. (C) Levels of organoid formation in 3D cultures incubated with GPNMB (0–100 ng/mL) for conditions in A. (D) Photomicrographs of organoids for conditions in C without or with GPNMB (100 ng/mL). Scale bar: 80 μm. (E) Organoid formation for conditions in C but using incubation with GPNMB (10 ng/mL) with or without anti-CD44 mAb or control IgG. (F) Levels of Cxcl17 and Il33 mRNA for conditions in C. (G) Protocol scheme for human tracheobronchial epithelial cell isolation and 3D culture. (H) Photomicrographs of organoids for conditions in G without or with GPNMB (100 ng/mL). Scale bar: 80 μm. (I) Levels of organoid formation and CXCL17 and IL33 mRNA for conditions in G with GPNMB (0–100 ng/mL). For B–E and G, results are representative of non-disease control individuals (n = 6–8 per condition). *P < 0.05 by ANOVA and Tukey’s correction.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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