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Sci Adv. 2019 Jul 17;5(7):eaav3270. doi: 10.1126/sciadv.aav3270. eCollection 2019 Jul.

Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis.

Author information

1
Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
2
Proteomics Center, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.
3
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
4
Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council (CNR) of Italy, Palermo, Italy.
5
Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Abstract

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.

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