RT Journal Article SR Electronic T1 Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaav3270 DO 10.1126/sciadv.aav3270 VO 5 IS 7 A1 van de Vlekkert, Diantha A1 Demmers, Jeroen A1 Nguyen, Xinh-Xinh A1 Campos, Yvan A1 Machado, Eda A1 Annunziata, Ida A1 Hu, Huimin A1 Gomero, Elida A1 Qiu, Xiaohui A1 Bongiovanni, Antonella A1 Feghali-Bostwick, Carol A. A1 d’Azzo, Alessandra YR 2019 UL http://advances.sciencemag.org/content/5/7/eaav3270.abstract AB Lysosomal exocytosis is a ubiquitous process negatively regulated by neuraminidase 1 (NEU1), a sialidase mutated in the glycoprotein storage disease sialidosis. In Neu1−/− mice, excessive lysosomal exocytosis is at the basis of disease pathogenesis. Yet, the tissue-specific molecular consequences of this deregulated pathway are still unfolding. We now report that in muscle connective tissue, Neu1−/− fibroblasts have features of myofibroblasts and are proliferative, migratory, and exocytose large amounts of exosomes. These nanocarriers loaded with activated transforming growth factor–β and wingless-related integration site (WNT)/β-catenin signaling molecules propagate fibrotic signals to other cells, maintaining the tissue in a prolonged transitional status. Myofibroblast-derived exosomes fed to normal fibroblasts convert them into myofibroblasts, changing the recipient cells’ proliferative and migratory properties. These findings reveal an unexpected exosome-mediated signaling pathway downstream of NEU1 deficiency that propagates a fibrotic disease and could be implicated in idiopathic forms of fibrosis in humans.