Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer’s Disease

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

“…An excessive microglial activation damages the surrounding healthy neural tissue and induces the release of alarmins and DAMPs from dead or dying neurons, which in turn, activates microglia enabling creation of "positive inflammatory loop" in CNS, that results in a massive and progressive loss of neurons [61]. In line with these findings, Ding and colleagues recently revealed that modulation of microglial activity was the main mechanism responsible for beneficial effects of MSC-EVs in alleviation of Alzheimer's disease (AD) [62]. Excessive accumulation of the amyloid-β peptide (Aβ) in the brain is considered as the most common pathological characteristic of AD, which triggers dysfunction of cognitive behavior [63].…”

“…Significantly increased levels of NEP, IDE, IL-10 and TGF-β, and greatly reduced concentration of inflammatory cytokines (TNF-α and IL-1β) were noticed in the brains of MSC-Exos-treated AβPP/PS1 mice, indicating that MSC-Exos induce conversion of microglia from inflammatory M1 towards immunosuppressive M2 phenotype [62]. MSC-Exo-induced alternative microglial activation was confirmed in vitro, since significantly higher concentration of IL-10 and TGF-β and lower concentration of TNF-α and IL-1β were measured in supernatants of MSC-Exo-treated BV2 murine microglia cells [62].…”

“…Excessive accumulation of the amyloid-β peptide (Aβ) in the brain is considered as the most common pathological characteristic of AD, which triggers dysfunction of cognitive behavior [63]. Intravenously injected Exos, obtained from human umbilical cord-derived MSCs, managed to reduce Aβ deposition and increased spatial learning and memory function in AβPP/PS1 transgenic mice, used as murine model of AD [62]. Additionally, Bodart-Santos and colleagues recently revealed that MSC-EVs prevented neuronal damage in AD by suppressing oxidative stress-induced injury of hippocampal neurons [64].…”

“…MSC-Exos induced polarization of microglia towards immunosuppressive M2 phenotype. Significantly higher number chitinase 3-like 3, arginase-1 and mannose receptor C type 1 (MRC1)-expressing M2 microglia cells were found in the brains of MSC-Exos-treated AβPP/PS1 mice [62]. M2 cells produce Aβ-degrading enzymes (neprilysin (NEP) and insulin-degrading enzyme (IDE)) and anti-inflammatory cytokines (IL-10 and TGF-β), contributing to the reduced Aβ deposition and alleviated inflammation [61].…”

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells

“…Notable studies have reported that BM-MSC exosomes could repair spinal cord injury by suppressing the activation of A1 neurotoxic reactive astrocytes induced by activated microglia (86) or by inhibiting the complement system (105) and the NF-κB signaling pathway (46,57,105). Meanwhile, SC-EVs have been observed to polarize microglia from classic M1 to antiinflammatory M2 phenotypes (59,85,106,107), which might be attributed to the targeted suppression of the 3 ′ -UTR mRNA expression in Beclin-1 and Atg5 and inhibition of autophagymediated microglial polarization toward pro-inflammatory state by miR-30d-5p-expressing EVs (59) ( Table 1). Thus, SC-EVs create a microenvironment conducive to nerve cell repair by inducing expression of microglial immunotolerance phenotypes in NS diseases.…”