Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines

Abstract

The therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

Human umbilical cord derived mesenchymal stem cells overexpressing HO‐1 attenuate neural injury and enhance functional recovery by inhibiting inflammation in stroke mice

“…Studies on MSC transplantation into animals or humans with inflammatory diseases have shown that MSCs have a strong inhibitory effect on the activation and proliferation of T cells and T cell‐mediated inflammatory responses. There is a growing consensus that the immunosuppressive capacity of MSCs is not structural but rather permitted by inflammatory cytokines in the microenvironment 40 . Engineered MSCs exhibited good performance in regulating inflammatory cytokines in the microenvironment; however, their nonstructural anti‐inflammatory ability in the CNS remains to be explored 18 .…”

Exosomes-based therapy of stroke, an emerging approach toward recovery

“…Like different stem cell types, Exo are eligible to promote healing procedures inside the nervous system after ischemic changes via several mechanism transfers of neurotrophic factors, induction of angiogenesis, and neurogenesis in which the combination of whole cell-based transplantation with Exo exhibit significant regenerative capacity. Besides these effects, Exo can control the production of pro-inflammatory cytokines, gliosis, and astrocyte and microglia polarization in the injured sites [ 28 , 29 ]. The existence of specific genetic cargo such as miRNAs inside Exo lumen helps these nanoparticles to exert efficient therapeutic effects upon reaching to the target cells [ 30 , 31 ].…”

The Role of MSCs and Cell Fusion in Tissue Regeneration

“…Due to their immunomodulating and anti-inflammatory capacity, MSCs and their derivates are thought to be possible therapeutic agents for neurological disorders [61]. Various studies investigated the effect of MSCs or MSC derived EVs on MS in experimental autoimmune encephalomyelitis (EAE), an animal model of MS [60,[62][63][64][65]. This includes Ahmadvand Koohsari et al, who demonstrated that the application of EVs from human umbilical cord blood MSCs reduced the amount of pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, leading to an alleviation of the disease [62].…”

“…Various studies investigated the effect of MSCs or MSC derived EVs on MS in experimental autoimmune encephalomyelitis (EAE), an animal model of MS [60,[62][63][64][65]. This includes Ahmadvand Koohsari et al, who demonstrated that the application of EVs from human umbilical cord blood MSCs reduced the amount of pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, leading to an alleviation of the disease [62]. Furthermore, the use of MSC-EVs, which have been stimulated by IFN-γ beforehand, enhanced motor skills and reduced neuroinflammation and demyelination, suggesting that stimulation of MSCs with pro-inflammatory cytokines might be necessary for an improved healing potential [63].…”