Mesenchymal Stem Cell-Derived Extracellular Vesicles and Their Therapeutic Use in Central Nervous System Demyelinating Disorders

Abstract

Autoimmune demyelinating diseases-including multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein-associated disease, acute disseminated encephalomyelitis, and glial fibrillary acidic protein (GFAP)-associated meningoencephalomyelitis-are a heterogeneous group of diseases even though their common pathology is characterized by neuroinflammation, loss of myelin, and reactive astrogliosis. The lack of safe pharmacological therapies has purported the notion that cell-based treatments could be introduced to cure these patients. Among stem cells, mesenchymal stem cells (MSCs), obtained from various sources, are considered to be the ones with more interesting features in the context of demyelinating disorders, given that their secretome is fully equipped with an array of anti-inflammatory and neuroprotective molecules, such as mRNAs, miRNAs, lipids, and proteins with multiple functions. In this review, we discuss the potential of cell-free therapeutics utilizing MSC secretome-derived extracellular vesicles-and in particular exosomes-in the treatment of autoimmune demyelinating diseases, and provide an outlook for studies of their future applications.

Keywords: autoimmune demyelinating diseases; exosomes; extracellular vesicles; mesenchymal stem cells; miRNAs; neuroinflammation; secretome.

Figure 1

Molecular cargo of EVs from unstimulated (Native-EVs) and IFN-γ (IFN-γ-EVs and hypoxia (H-EVs)-primed MSCs. Treatment with IFN-γ and hypoxia implicates the high expression of specific immunomodulatory molecules, indicated by an upward arrow. Preconditioning of MSCs with IFN-γ causes an overexpression of indoleamine 2,3- dioxygenase 1 (IDO-1) mRNA, miR-467f, miR-466q, annexin A4 (ANXA4), and histones, while hypoxic conditions cause an increase in miR-216a. Moreover, IFN-γ-EVs contain several apolipoproteins and complement-related proteins. Created with BioRender.com.

Figure 2

MSC-EVs’ in vivo and in vitro effects: Treatment with MSC-EVs showed their immunomodulatory, neuroprotective, and anti-inflammatory effects by enhancing Treg numbers and neurite outgrowth, and by diminishing pro-inflammatory cytokines (e.g., TNF-α, IL-1β) in favor of anti-inflammatory ones (e.g., IL-10, TGF-β), in EAE animal models (injecting MOG_35–55 peptide/pertussis toxin, TMEV, or spinal cord homogenates) and in different cell cultures. Created with BioRender.com.