FGF10-FGFR2B Signaling Generates Basal Cells and Drives Alveolar Epithelial Regeneration by Bronchial Epithelial Stem Cells after Lung Injury

Abstract

Summary Idiopathic pulmonary fibrosis is a common form of interstitial lung disease resulting in alveolar remodeling and progressive loss of pulmonary function because of chronic alveolar injury and failure to regenerate the respiratory epithelium. Histologically, fibrotic lesions and honeycomb structures expressing atypical proximal airway epithelial markers replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Bronchial epithelial stem cells (BESCs) can give rise to AT2 and AT1 cells or honeycomb cysts following bleomycin-mediated lung injury. However, little is known about what controls this binary decision or whether this decision can be reversed. Here we report that inactivation of Fgfr2b in BESCs impairs their contribution to both alveolar epithelial regeneration and honeycomb cysts after bleomycin injury. By contrast overexpression of Fgf10 in BESCs enhances fibrosis resolution by favoring the more desirable outcome of alveolar epithelial regeneration over the development of pathologic honeycomb cysts.

Temporospatial Expression of Fgfr1 and 2 During Lung Development, Homeostasis, and Regeneration

“…We found Fgfr2 to be higher in the distal airway club cells compared to proximal airway club cells at 3 and 6 weeks after bleomycin injury ( Figures 6A-C, P). These findings are consistent with our previous report on the role of Fgf10-Fgfr2 signaling in alveolar epithelial regeneration by bronchial epithelial stem cells (Yuan et al, 2019). We found similarly high expression of Fgfr2 in regeneration AT2 cells upon bleomycin injury ( Figures 6D-F, P and S2) and in proximal neo-basal cells but significantly lower expression of Fgfr2 in more distal neo-basal cells ( Figures 6G-I, P), consistent with our previous finding that Fgfr2 is required for the development of neo-basal cells upon bleomycin injury and that increased Fgf10 signaling can drive these cells along the AT2 cell lineage whereas reduced Fgfr2 signaling leads to their differentiation into AT1 cells (Yuan et al, 2019).…”

“…During postnatal lung development, we found strong Fgfr2 expression in AT2 cells and strong Fgfr1 signaling in adjacent mesenchymal alveolar niche cells or lipofibroblasts ( Figures 4A-D, U-Y). Interestingly, Fgfr2 expression was still present in AT1 cells but at lower level than in AT2 cells (Figures 4E-H, Y), which is consistent with an important role for Fgfr2 signaling in AT2 stem cell maintenance (Yuan et al, 2019). We further found Fgfr2 expression in club cells ( Figures 4M-P…”

“…in myofibroblasts upon bleomycin injury ( Figures 6J-O) consistent with them being derived from lipofibroblasts (El Agha et al, 2017;Yuan et al, 2019).…”

“…Fgfr1 and Fgfr2, two of the four fibroblast growth factor receptors, play important roles during lung development and regeneration, often mediating reciprocal signaling between the epithelium and mesenchyme via their ligand Fgfs (Jaskoll et al, 2005;MacKenzie et al, 2015;Balasooriya et al, 2017;Yuan et al, 2019). Our recent studies showed that Fgf10-Fgfr2b signaling is critical for generating basal cells and to drive alveolar epithelial regeneration after bleomycin injury in the lung (Yuan et al, 2019). Both Fgfr1 and Fgfr2 are also considered as potential targets for lung cancer therapy (Weiss et al, 2010;Theelen et al, 2016).…”

3D cell culture models demonstrate a role for FGF and WNT signaling in regulation of lung epithelial cell fate and morphogenesis

“…Still, we observed significantly higher expression of markers of all lung cell lineages, suggesting that FGF10 promoted organoid differentiation to both airway and distal lung epithelium. This is consistent with the reported role of FGF10 in regulation of lung progenitor differentiation based on the developmental context (Volckaert et al, 2013) as well as during homeostasis and in regeneration (Volckaert et al, 2017; Yuan et al, 2019).…”