MiR-219a-5p Enriched Extracellular Vesicles Induce OPC Differentiation and EAE Improvement More Efficiently Than Liposomes and Polymeric Nanoparticles

Abstract

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood–brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients.

Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels

“…Reduced levels of miR-219 have been observed in the cerebrospinal fluid of Multiple Sclerosis (MS) patients [ 31 ] and may contribute to impaired OPC differentiation and failed remyelination [ 32 , 34 ]. Conversely, increasing the miR-219 levels leads to enhanced OPC maturation and it could serve as a viable strategy towards remyelination [ 47 , 48 , 49 , 50 , 51 , 52 ]. Overall, miR-219 is an established enhancer of oligodendrogenesis and a promising target for remyelination.…”

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

“…They readily cross the BBB with low immunoreactivity, see reduced clearance by the mononuclear phagocyte system compared with synthetic nanoparticles, and can be selected or bioengineered to be preferentially taken up by particular cell types, such as via modification of the surface protein profile [ 125 ]. Indeed, EVs isolated from HEK293 cells engineered via lentiviral infection to express miR-219a, cross the BBB, promote OPC differentiation and improve clinical score in EAE, outperforming both PLGA nanoparticles and DSPC liposomes carrying miR-219a mimics [ 126 ]. Exosomes taken from dendritic cells pre-treated with IFNγ promote ex vivo remyelination and in vivo myelination compared with untreated control exosomes, an effect associated with increased exosomal miR-219 cargo [ 127 ].…”

Promising Nanotechnology Approaches in Treatment of Autoimmune Diseases of Central Nervous System

“…MicroRNAs were postulated as a promising tool to induce OPC differentiation and, therefore, remyelination, albeit exhibiting significant limitations in terms of the administration of microRNAs to the CNS. Osorio-Querejeta et al [85] utilized three different categories of nanosystems for miR-219a-5p encapsulation, release, and remyelination promotion, namely, liposomes from 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC) lipid (Avanti Polar Lipids, Alabaster, AL, USA), poly(lactic-co-glycolic) acid polymeric nanoparticles, and finally biologically engineered extracellular vesicles overexpressing miR-219a-5p, which are also lipid-based, due to their biological origin. Extracellular vesicles are biological delivery systems that contain other proteins, lipids, and genetic material, apart from RNA, which can be integrated into the cell in several ways, and which contain microRNA-processing molecules.…”