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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Dependovirus / genetics
  • Disease Models, Animal
  • Disease Susceptibility*
  • Exocytosis
  • Exosomes / metabolism*
  • Fibroblasts / metabolism
  • Fibrosis / etiology*
  • Fibrosis / metabolism*
  • Fibrosis / pathology
  • Fibrosis / therapy
  • Gene Transfer Techniques
  • Genetic Therapy
  • Humans
  • Immunohistochemistry
  • Lysosomes / metabolism*
  • Mice
  • Mucolipidoses
  • Myofibroblasts / metabolism
  • Signal Transduction*
  • Transforming Growth Factor beta / metabolism
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism


  • Biomarkers
  • Transforming Growth Factor beta
  • Wnt Proteins
  • beta Catenin

Supplementary concepts

  • Neuraminidase 1 deficiency