Complex urban atmosphere alters alveolar stem cells niche properties and drives lung fibrosis

• Published in: American journal of physiology. Lung cellular and molecular physiology 2023-10, Vol.325 (4), p.L447-L459
• Main Authors: Belgacemi, Randa, Ribeiro Baptista, Bruno, Justeau, Grégoire, Toigo, Marylène, Frauenpreis, Andrew, Yilmaz, Rojda, Der Vartanian, Audrey, Cazaunau, Mathieu, Pangui, Edouard, Bergé, Antonin, Gratien, Aline, Macias Rodriguez, Juan Camilo, Bellusci, Saverio, Derumeaux, Geneviève, Boczkowski, Jorge, Al Alam, Denise, Coll, Patrice, Lanone, Sophie, Boyer, Laurent
• Format: Article
• Language: English
• Subjects: Alveolar Epithelial Cells - metabolism; Animals; Cell Differentiation; Collagen - metabolism; Epithelial Cell Adhesion Molecule - metabolism; Life Sciences; Lung - metabolism; Mice; Pulmonary Fibrosis - pathology; Stem Cells
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00061.2023

There is growing evidence suggesting that urban pollution has adverse effects on lung health. However, how urban pollution affects alveolar mesenchymal and epithelial stem cell niches remains unknown. This study aimed to determine how complex representative urban atmospheres alter alveolar stem cell niche properties. Mice were placed in an innovative chamber realistically simulating the atmosphere of a megalopolis, or "clean air," for 7 days. Lungs were collected, and fibroblasts and epithelial cells (EpCAM ) were isolated. Proliferative capacities of fibroblasts were tested by population doubling levels (PDL), and microarray analyses were performed. Fibroblasts and EpCAM cells from exposed, nonexposed, or naive mice were cocultured in organoid assays to assess the stem cell properties. Collagen deposition (Sirius red), lipofibroblasts (ADRP, COL1A1), myofibroblasts (αSMA), alveolar type 2 cells (AT2, SFTPC ), and alveolar differentiation intermediate cell [ADI, keratin-8-positive (KRT8 )/claudin-4-positive (CLDN4 )] markers were quantified in the lungs. Fibroblasts obtained from mice exposed to urban atmosphere had lower PDL and survival and produced fewer and smaller organoids. Microarray analysis showed a decrease of adipogenesis and an increase of genes associated with fibrosis, suggesting a lipofibroblast to myofibroblast transition. Collagen deposition and myofibroblast number increased in the lungs of urban atmosphere-exposed mice. AT2 number was reduced and associated with an increase in ADI cells KRT8 /CLDN4 . Furthermore, EpCAM cells from exposed mice also produced fewer and smaller organoids. In conclusion, urban atmosphere alters alveolar mesenchymal stem cell niche properties by inducing a lipofibroblast to myofibroblast shift. It also results in alveolar epithelial dysfunction and a fibrotic-like phenotype. Urban pollution is known to have major adverse effects on lung health. To assess the effect of pollution on alveolar regeneration, we exposed adult mice to a simulated high-pollution urban atmosphere, using an innovative CESAM simulation chamber (Multiphase Atmospheric Experimental Simulation Chamber, https://cesam.cnrs.fr/). We demonstrated that urban atmosphere alters alveolar mesenchymal stem cell niche properties by inducing a lipofibroblast to myofibroblast shift and induces alveolar epithelial dysfunction.