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

Iñaki Osorio-Querejeta,Leslie A Nash,Felipe Goñi-De-Cerio,Susana Carregal-Romero,Laura Moles,Goran Bijelic,Ander Egimendia,Marco Möller,David Otaegui,M Betanzos,Matthew Wood,Ainhoa Alberro,Irantzu Llarena,Pedro Ramos-Cabrer,Leire Iparraguirre,Imre Mäger,Maider Muñoz-Culla,Ana Ayerdi-Izquierdo

doi:10.3390/pharmaceutics12020186

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.

Highlights

Myelin is a lipid membrane formed by oligodendrocytes (OL) in the central nervous system (CNS)
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
In order to obtain fluorescent extracellular vesicles (EVs) for up-take and blood–brain barrier (BBB) crossing experiments, non-enriched extracellular vesicles (Ne-EVs) were labelled with CM-Dil (Celltracker CM-DiI, #C7001, Thermo Fisher) as previously described [18], obtaining Ne-EVs-CM-Dil

Summary

Introduction

Myelin is a lipid membrane formed by oligodendrocytes (OL) in the central nervous system (CNS). In several diseases myelin is damaged causing an incorrect nerve impulse transmission and an imbalance in the homeostasis of axons, which can lead to neurodegeneration. In the first stages of the disease, myelin can be endogenously restored in a process called remyelination. To perform this task, oligodendrocyte precursor cells (OPC) proliferate, migrate to the lesions, differentiate to oligodendrocytes and extend myelin’s sheaths around axons [2]. When the disease progresses, the remyelination capacity of OL decreases and tends to fail The reasons why this occurs are still not clear but it is thought to be related with the absence, insufficient migration or poor differentiation of OPCs [3,4]

Methods

Results

Conclusion