Therapeutic potential of extracellular vesicles derived from human mesenchymal stem cells in a model of progressive multiple sclerosis

Abstract

Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication and as possible therapeutic agents in inflammation-mediated demyelinating diseases, including multiple sclerosis (MS). In the present study, we investigated whether intravenously administered EVs derived from mesenchymal stem cells (MSCs) from human adipose tissue might mediate recovery in Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease, a progressive model of MS. SJL/J mice were subjected to EV treatment once the disease was established. We found that intravenous EV administration improved motor deficits, reduced brain atrophy, increased cell proliferation in the subventricular zone and decreased inflammatory infiltrates in the spinal cord in mice infected with TMEV. EV treatment was also capable of modulating neuroinflammation, given glial fibrillary acidic protein and Iba-1 staining were reduced in the brain, whereas myelin protein expression was increased. Changes in the morphology of microglial cells in the spinal cord suggest that EVs also modulate the activation state of microglia. The clear reduction in plasma cytokine levels, mainly in the Th1 and Th17 phenotypes, in TMEV mice treated with EVs confirms the immunomodulatory ability of intravenous EVs. According to our results, EV administration attenuates motor deficits through immunomodulatory actions, diminishing brain atrophy and promoting remyelination. Further studies are necessary to establish EV delivery as a possible therapy for the neurodegenerative phase of MS.

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

“…Modulation of microglial activity was mainly responsible for beneficial effects of MSC-Exos in alleviation of multiple sclerosis (MS), inflammation-mediated demyelinating disease [65]. Significantly improved motor function was noticed in Theiler's murine encephalomyelitis virus (TMEV)-infected mice that received MSC-EVs [65].…”

“…Modulation of microglial activity was mainly responsible for beneficial effects of MSC-Exos in alleviation of multiple sclerosis (MS), inflammation-mediated demyelinating disease [65]. Significantly improved motor function was noticed in Theiler's murine encephalomyelitis virus (TMEV)-infected mice that received MSC-EVs [65]. Remarkably reduced number of Iba-1-positive microglia cells was observed in the brains of TMEV+MSC-EV-treated mice compared to TMEV-only treated animals [65].…”

“…Significantly improved motor function was noticed in Theiler's murine encephalomyelitis virus (TMEV)-infected mice that received MSC-EVs [65]. Remarkably reduced number of Iba-1-positive microglia cells was observed in the brains of TMEV+MSC-EV-treated mice compared to TMEV-only treated animals [65]. Importantly, MSC-EVs altered cytokine milieu in TMEV-infected mice.…”

Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases

“…In multiple sclerosis, an autoimmune disease of the central nervous system characterized by localized neuro-axonal degenerations, the function of regulatory T cells is impaired. A potential for multiple sclerosis and its therapy is also demonstrated by EVs generated from human MSCs [42]. Analysis of cerebrospinal fluid in multiple sclerosis has demonstrated an enrichment of EVs in the plasma, which is important for the disease [40], while EVs containing interleukin (IL)-4 modulate neuro-inflammation [41].…”

“…Analysis of cerebrospinal fluid in multiple sclerosis has demonstrated an enrichment of EVs in the plasma, which is important for the disease [40], while EVs containing interleukin (IL)-4 modulate neuro-inflammation [41]. A potential for multiple sclerosis and its therapy is also demonstrated by EVs generated from human MSCs [42]. In another disease of the central nervous system, amyotrophic lateral sclerosis, neuronal degeneration is located in multiple areas.…”