Pathogenic expansion: fibroblast proliferation fuels fibrosis

Pulmonary fibrosis, an unrelenting disease of lung scarring, has been associated with the expansion of a profibrotic fibroblast population and extensive extracellular matrix deposition. In this issue, Molina and colleagues provide foundational mechanistic evidence that fibroblast proliferation itself is a critical driver of fibrosis. Using lineage tracing in preclinical fibrosis models, the authors showed that naive Scube2+ alveolar fibroblasts underwent a profibrotic phenotypic switch prior to proliferating within areas of fibrotic remodeling. Induction of apoptosis via Esco2 deletion or directly preventing proliferation via Ect2 deletion in these fibroblasts attenuated fibrosis. Complementary analyses on explanted human lung tissue confirmed translational relevance, collectively providing compelling evidence for the importance of fibroblast proliferation in fibrotic disease.