Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease. A maladaptive epithelium due to chronic injury is a prominent feature and contributor to pathogenic cellular communication in IPF. Recent data highlight the concept of a “reprogrammed” lung epithelium as critical in the development of lung fibrosis. Extracellular vesicles (EVs) are potent mediators of cellular crosstalk, and recent evidence supports their role in lung pathologies, such as IPF. Here, we demonstrate that syndecan-1 is overexpressed by the epithelium in the lungs of patients with IPF and in murine models after bleomycin injury. Moreover, we find that syndecan-1 is a profibrotic signal that alters alveolar type II cell phenotypes by augmenting TGF-β and Wnt signaling among other profibrotic pathways. Importantly, we demonstrate that syndecan-1 controls the packaging of several antifibrotic microRNAs into EVs that have broad effects over several fibrogenic signaling networks as a mechanism of regulating epithelial plasticity and pulmonary fibrosis. Collectively, our work reveals new insight into how EVs orchestrate cellular signals that promote lung fibrosis and demonstrate the importance of syndecan-1 in coordinating these programs.