Complex Urban Atmospheres alters Alveolar Stem Cells Niche Properties and drives Lung Fibrosis

Science and Research

INTRODUCTION: 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. AIM: Determine how complex representative urban atmospheres alter alveolar stem cell niche properties. METHODS: 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. Fibroblasts proliferative capacities were tested by population doubling levels (PDL) and microarray analyses were performed. Fibroblasts and EpCAM+ cells from exposed, non-exposed or naive mice were co-cultured in organoid assays to assess the stem cell properties. Collagen deposition (Sirius red), lipofibroblasts (ADRP), myofibroblasts (COL1A1, αSMA), alveolar type 2 cells (AT2, SFTPC(+)) and alveolar differentiation intermediate cell (ADI, KRT8(+)/CLDN4(+)) markers were quantified in the lungs. RESULTS: 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 lung of urban atmosphere exposed mice. AT2 number was reduced and associated with an increase of ADI cells KRT8(+)/CLDN4(+). Furthermore, EpCAM+ cells from exposed mice also produced fewer and smaller organoids. CONCLUSIONS: 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 phenotype.