Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury
Thomas Volckaert, … , Saverio Bellusci, Stijn P. De Langhe
Thomas Volckaert, … , Saverio Bellusci, Stijn P. De Langhe
Published October 10, 2011
Citation Information: J Clin Invest. 2011;121(11):4409-4419. https://doi.org/10.1172/JCI58097.
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Research Article Pulmonology

Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury

Abstract

During lung development, parabronchial SMC (PSMC) progenitors in the distal mesenchyme secrete fibroblast growth factor 10 (Fgf10), which acts on distal epithelial progenitors to promote their proliferation. β-catenin signaling within PSMC progenitors is essential for their maintenance, proliferation, and expression of Fgf10. Here, we report that this Wnt/Fgf10 embryonic signaling cascade is reactivated in mature PSMCs after naphthalene-induced injury to airway epithelium. Furthermore, we found that this paracrine Fgf10 action was essential for activating surviving variant Clara cells (the cells in the airway epithelium from which replacement epithelial cells originate) located at the bronchoalveolar duct junctions and adjacent to neuroendocrine bodies. After naphthalene injury, PSMCs secreted Fgf10 to activate Notch signaling and induce Snai1 expression in surviving variant Clara cells, which subsequently underwent a transient epithelial to mesenchymal transition to initiate the repair process. Epithelial Snai1 expression was important for regeneration after injury. We have therefore identified PSMCs as a stem cell niche for the variant Clara cells in the lung and established that paracrine Fgf10 signaling from the niche is critical for epithelial repair after naphthalene injury. These findings also have implications for understanding the misregulation of lung repair in asthma and cancer.

Authors

Thomas Volckaert, Erik Dill, Alice Campbell, Caterina Tiozzo, Susan Majka, Saverio Bellusci, Stijn P. De Langhe

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Figure 1

Wnt7b expressed by surviving ciliated cells induces Fgf10 expression in PSMCs 3 days after naphthalene-mediated Clara cell injury.

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Wnt7b expressed by surviving ciliated cells induces Fgf10 expression in ...
(A–C) Immunostaining for proliferation marker BrdU and SMC marker α-SMA on 2-month-old WT lungs 3 days after corn oil treatment (A), WT lungs 3 days after naphthalene (npt) treatment (B), and Rosa26-rtTa;Tet-Dkk1 lungs 3 days after naphthalene treatment (C). (D–F) β-gal staining on 2-month-old TOPGAL lungs 3 days after corn oil treatment (D), TOPGAL lungs 3 days after naphthalene treatment (E), and Rosa26-rtTa;Tet-Dkk1;TOPGAL lungs 3 days after naphthalene treatment (F). Arrow in E denotes TOPGAL activation in PSMCs. (G–I) β-gal staining on 2-month-old Fgf10LacZ lungs 3 days after corn oil treatment (G), Fgf10LacZ lungs 3 days after naphthalene treatment (H), and Rosa26-rtTa;Tet-Dkk1;Fgf10LacZ lungs 3 days after naphthalene treatment (I). Insets are enlarged ×4. Note that we identified the blue cells in alveolar compartment as lipofibroblasts (S.P. De Langhe, unpublished observations). (J and K) Immunostaining for ciliated cell marker β-tubulin and Wnt7b on 2-month-old WT lungs 3 days after corn oil treatment (J) or naphthalene treatment (K). Insets are enlarged ×3. (L) qPCR analysis of relative Wnt7b and Wnt3a mRNA abundance in 2-month-old WT lungs 3 days after treatment with corn oil versus naphthalene. **P < 0.01 vs. respective control. n = 3. Scale bars: 100 μm (A–C, J, and K); 250 μm (D–F); 200 μm (G–I).