Neuroprotection mediated by cystatin C-loaded extracellular vesicles

• Published in: Scientific reports Vol. 9; no. 1; pp. 11104 - 10
• Main Authors: Pérez-González, Rocío, Sahoo, Susmita, Gauthier, Sebastien A., Kim, Yohan, Li, Meihua, Kumar, Asok, Pawlik, Monika, Benussi, Luisa, Ghidoni, Roberta, Levy, Efrat
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-07-2019; Nature Publishing Group
• Subjects: 13; 13/106; 14/1; 14/19; 14/28; 14/34; 631/378/1831; 631/80/313/1481; 64; 64/110; 64/60; 82/29; 82/51; Animals; Brain - metabolism; Cell death; Cells, Cultured; Central nervous system; Cystatin C; Cystatin C - metabolism; Exosomes; Exosomes - metabolism; Extracellular vesicles; Extracellular Vesicles - metabolism; Humanities and Social Sciences; Humans; Lysosomes - metabolism; Mice; Mice, Transgenic; multidisciplinary; Nervous system; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurons - metabolism; Neuroprotection; Neuroprotection - physiology; Neurotoxicity; Science; Science (multidisciplinary); Secretion; Smooth muscle; Starvation; Transgenic mice
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47524-7

Cystatin C (CysC) is implicated in neuroprotection and repair in the nervous system in response to diverse neurotoxic conditions. In addition to being secreted from cells in a soluble form, CysC is released by cells in association with extracellular vesicles (EVs), including exosomes. We demonstrate that EVs containing CysC protect cultured cells from starvation-induced death. Moreover, while EVs secreted by CysC-deficient cells were not protective, EVs secreted by CysC-deficient cells treated with exogenous human CysC significantly enhanced the survival of the cells. CysC also plays a role in modulating the secretion of EVs, enhancing secretion of EVs by primary cortical neurons and primary cortical smooth muscle cells. Confirming these
in vitro
findings, higher EV levels were observed in the brain extracellular space of transgenic mice expressing human CysC as compared to littermate controls. Regulation of cell-secreted EV levels and content in the brain is likely to be essential to maintaining normal brain function. We propose that enhanced EV release could rescue the deleterious effects of dysfunction of the endosomal-lysosomal system in neurodegenerative disorders. Moreover, a higher level of CysC-loaded EVs released from cells in the central nervous system has important protective functions, representing a potential therapeutic tool for disorders of the central nervous system.