Fibroblast-derived osteoglycin promotes alveolar epithelial cell repair

There is an increasing need for pharmacological treatments that target defective epithelial repair in chronic diseases, such as chronic obstructive pulmonary disease. The mesenchymal niche plays a major regulatory role in guiding epithelial progenitor cell activation during repair. We persuaded that the secreted factors involved in this interaction hold potential as drug targets. In this study, we utilized a proteomics-guided drug discovery strategy, leveraging the secretome of lung fibroblasts, to uncover drug targets affecting epithelial progenitor behavior. Using lung organoids, we identified several ligands with regenerative potential, of which the matrix protein osteoglycin (OGN) surprisingly had the most profound effect. RNA sequencing revealed that OGN promoted alveolar epithelial type II cell differentiation, whilst increasing reactive oxygen species detoxification, reducing senescence, and enhancing growth factor-mediated fibroblast- epithelial crosstalk. In accordance with this OGN protein expression was reduced in damaged lung tissue of COPD patients and in smoke-exposed mice. Additionally, we found an active fragment of OGN comprising the leucine-rich repeat regions 4-7 to have comparable regenerative potential in regulating lung organoid formation. The active fragment of OGN ameliorated elastase-induced lung injury in precision-cut lung slices (PCLS) and improved lung function in mice. These findings identify lung fibroblast-derived OGN as a matrix protein supporting alveolar epithelial growth and its active fragment as a promising therapeutic target for epithelial cell repair in individuals with accelerated tissue damage.