Intravenous administration of anti-inflammatory exosomes from human mesenchymal stem cells suppress lipopolysaccharide-induced neuroinflammation in mice

SANTA-CRUZ D.; YANNARELLI G.; MALVICINI R.; PACIENZA N.; PROCKOP D.

Mar del Plata

Congreso; LXIII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica (SAIC)

Neuroinflammation is an important component of many diseases of the brain. Recently there has been great interest in the therapeutic potential of the small extracellular vesicles defined as exosomes. Here we investigated the suppression of neuroinflammation by human mesenchymal stem cells (MSCs)-derived exosomes in a classic inflammatory murine model induced by intravenous administration of a low dose of LPS (2.5 mg/Kg). Human MSCs were cultured in a chemically defined protein-free medium for 48 h and CD63+CD81+ exosomes were isolated by anion exchange chromatography. Nanoparticle tracking analysis showed a single peak of exosomes (mode size 92.9±2.4 nm) without the presence of other types of vesicles. Exosomes demonstrated anti-inflammatory activity in-vitro by suppressing the up-regulation of IL-1b in LPS-stimulated human brain microvascular endothelial cells in a dose-dependent manner. As expected, pro-inflammatory cytokines were significantly increased in spleen at 2 h and in hippocampus at 6 h after injection of LPS into mice. In hippocampus, IL-1b was mainly expressed by microglia (CD11b+ cells). Intravenously administered exosomes (4-6x109 exosomes/mouse) reduced the expression of IL-1b by 15.8%(p=0.006) and 37.5% (p=0.003) in spleen and hippocampus of LPS-treated mice, respectively. Moreover, exosomes supressed the up-regulation of the chemokine C-C motif ligand 2 (CCL2), an important mediator of inflammation, both in spleen (28.8%, p=0.008) and hippocampus (25.7%, p=0.0006). Exosomes pre-labeled with dye were found in microglia, indicating they had crossed the blood-brain barrier. In contrast, administration of dexamethasone (1.2 mg/Kg) decreased both IL-1b (30.5%, p=0.0002) and CCL2 (24.8%, p=0.007) in spleen but had no significant effect in the hippocampus of LPS-treated mice. The results demonstrated that intravenous administration of exosomes is more effective than dexamethasone in suppressing neuroinflammation induced by systemic administration of LPS. They therefore support previous indications that exosomes may be an effective therapy for any of the multiple causes of neuroinflammation.