Fibroblast-derived Osteoglycin Promotes Epithelial Cell Repair

ABSTRACT There is an urgent need for innovative pharmacological treatments targeting defective epithelial repair in chronic diseases, such as chronic obstructive pulmonary disease. The mesenchymal niche is a critical regulator in epithelial stem cell activation during repair. We hypothesized that secreted factors in this interaction are potent drug targets. Utilizing a cutting-edge proteomics-guided drug discovery strategy, we explored the lung fibroblast secretome to uncover impactful drug targets. Our lung organoid assays identified several regenerative ligands, with the secreted matrix protein osteoglycin (OGN) surprisingly showing the most profound effects. Transcriptomic analyses revealed that OGN enhances alveolar progenitor cell differentiation, boosts reactive oxygen species detoxification, reduces cellular senescence, and strengthens fibroblast-epithelial crosstalk. Critically, OGN expression was diminished in COPD patients and smoke-exposed mice. An active fragment of OGN, encompassing leucine-rich repeat regions 4-7, demonstrated regenerative potential akin to full-length OGN. This fragment significantly ameliorated elastase-induced lung injury precision-cut lung slices and improved lung function in vivo . These findings highlight lung fibroblast-derived OGN as a pivotal secreted protein for alveolar epithelial growth, positioning its active fragment as a promising therapeutic for epithelial repair in individuals with accelerated lung tissue damage.