Remyelinating effect driven by transferrin‐loaded extracellular vesicles

Abstract

Extracellular vesicles (EVs) are involved in diverse cellular functions, playing a significantrole in cell-to-cell communication in both physiological conditions and pathological scenarios.Therefore, EVs represent a promising therapeutic strategy. Oligodendrocytes(OLs) are myelinating glial cells developed from oligodendrocyte progenitor cells (OPCs)and damaged in chronic demyelinating diseases such as multiple sclerosis (MS). Glycoproteintransferrin (Tf) plays a critical role in iron homeostasis and has pro-differentiatingeffects on OLs in vivo and in vitro. In the current work, we evaluated the use of EVs astransporters of Tf to the central nervous system (CNS) through the intranasal (IN) route.For the in vitro mechanistic studies, we used rat plasma EVs. Our results show that EVTfenter OPCs through clathrin-caveolae and cholesterol-rich lipid raft endocytic pathways,releasing the cargo and exerting a pro-maturation effect on OPCs. These effects werealso observed in vivo using the animal model of demyelination induced by cuprizone(CPZ). In this model, IN administered Tf-loaded EVs isolated from mouse plasmareached the brain parenchyma, internalizing into OPCs, promoting their differentiation,and accelerating remyelination. Furthermore, in vivo experiments demonstrated thatEVs protected the Tf cargo and significantly reduced the amount of Tf required toinduce remyelination as compared to soluble Tf. Collectively, these findings unveil EVsas functional nanocarriers of Tf to induce remyelination.