CCN3-derived peptide BLR-200 impairs YAP activation and attenuates bleomycin-induced skin fibrosis through blocking the generation of Sfrp2-positive fibroblasts
Nguyen, J.; Peidl, A.; Chitturi, P.; McClintock, S. D.; Knibbs, R.; Zestranjyan, K.; Abdi, B. A.; Denomy, C.; Bhandari, P.; Carter, D. E.; Petitjean, M.; Varga, J.; Khanna, D.; Stratton, R. J.; Aslam, M. N.; Varani, J.; Riser, B. L.; Leask, A.
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An autocrine pro-adhesive/pro-contractile signaling loop, through the mechanosensitive transcriptional cofactor YAP, promotes fibrosis. The CCN family of matricellular proteins modify adhesive signaling. Of these, CCN3 is antifibrotic. We show that BLR-200, a CCN3-derived peptide, has anti-fibrotic properties in the bleomycin-induced model of scleroderma skin fibrosis. In vitro, BLR-200 delayed, but did not abolish, fibroblast adhesion to collagen and nuclear YAP localization. In vivo, BLR-200 prevented/treated bleomycin-induced skin fibrosis, and reduced bleomycin-induced expression of profibrotic genes including alpha-smooth muscle actin, CCN1 and CCN2. Lineage tracing and scRNA-seq analyses revealed that the myofibroblasts in this model were quantitatively derived from collagen-lineage Pi16+/Col15+ve fibroblasts. BLR-200 prevented myofibroblast differentiation in this model and trajectory of fibroblasts toward a Sfrp2-positive subset, a cell type associated with poor clinical outcome. BLR-200 impairs YAP activation in vitro and appearance of translationally-relevant fibroblast subtypes in vivo and is a novel anti-fibrotic agent for SSc skin fibrosis.
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