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– and wingless-related integration site (WNT)/-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.

Additional Metadata
Persistent URL dx.doi.org/10.1126/sciadv.aav3270, hdl.handle.net/1765/118550
Journal Science Advances
Citation
van de Vlekkert, D. (Diantha), Demmers, J.A.A, Nguyen, X.-X. (Xinh-Xinh), Campos, Y, Machado, E. (Eda), Annunziata, M, … D’Azzo, A. (Alessandra). (2019). Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis. Science Advances, 5(7). doi:10.1126/sciadv.aav3270