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.