Extracellular Vesicles of Mesenchymal Stromal Cells Can be Taken Up by Microglial Cells and Partially Prevent the Stimulation Induced by β-amyloid

Abstract

Mesenchymal stromal/stem cells (MSCs) have great capacity for immune regulation. MSCs provide protective paracrine effects, which are partially exerted by extracellular vesicles (EVs). It has been reported that MSCs-derived EVs (MSC-EVs) contain soluble factors, such as cytokines, chemokines, growth factors and even microRNAs, which confer them similar anti-inflammatory and regenerative effects to MSCs. Moreover, MSCs modulate microglia activation through a dual mechanism of action that relies both on cell contact and secreted factors. Microglia cells are the central nervous system immune cells and the main mediators of the inflammation leading to neurodegenerative disorders. Here, we investigated whether MSC-EVs affect the activation of microglia cells by β-amyloid aggregates. We show that the presence of MSC-EVs can prevent the upregulation of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and nitric oxide (NO). Both are up-regulated in neurodegenerative diseases representing chronic inflammation, as in Alzheimer’s disease. We demonstrate that MSC-EVs are internalized by the microglia cells. Further, our study supports the use of MSC-EVs as a promising therapeutic tool to treat neuroinflammatory diseases.Significance StatementIt has been reported that mesenchymal stromal/stem cells and MSC-derived small extracellular vesicles have therapeutic effects in the treatment of various degenerative and inflammatory diseases. Extracellular vesicles are loaded with proteins, lipids and RNA and act as intercellular communication mediators. Here we show that extracellular vesicles can be taken up by murine microglial cells. In addition, they partially reduce the activation of microglial cells against β-amyloid aggregates. This inhibition of microglia activation may present an effective strategy for the control/therapy of neurodegenerative diseases such as Alzheimer’s disease. Graphic Abstract

Extracellular vesicles and Alzheimer’s disease in the novel era of Precision Medicine: implications for disease progression, diagnosis and treatment

“…Mesenchymal stem cells (MSC) possess immunomodulatory and tissue regenerative properties and, therefore, have been suggested as therapeutic tools ( Pittenger et al, 2019 ). MSC-derived exosomes have been shown to decrease Aβ levels but also inhibit the Aβ-driven downregulation of synaptic plasticity-related genes ( Chen et al, 2021 ) or microglial activation ( Kaniowska et al, 2022 ). Other studies have also shown that MSC-derived EVs have beneficial effects in in vitro AD models by protecting neurons from oxidative stress and synaptic damage induced by Aβ oligomers ( Bodart-Santos et al, 2019 ; de Godoy et al, 2018 ).…”

High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia

“…Our novel microglia modulation assay provides a neuroinflammation-relevant context for assessing MSC-EVs from different priming conditions. MSC-EV modulation of microglia has been explored both in vitro and in vivo : ADMSC-EVs significantly decreased TNF-α secretion by microglia stimulated with lipopolysaccharide (LPS) or amyloid-beta (Aβ), a hallmark peptide of Alzheimer's disease [ 123 ]. In a triple transgenic mouse model of Alzheimer's disease, IFN-γ/TNF-α primed MSC-EVs delivered intranasally reduced microglia Iba-1 and CD68 (activation markers) expression and soma size, signifying an overall suppression of microglia activation [ 124 ].…”

High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia

“…Our novel microglia modulation assay provides a neuroinflammation-relevant context for assessing MSC-EVs from different priming conditions. MSC-EV modulation of microglia has been explored both in vitro and in vivo : ADMSC-EVs significantly decreased TNF-α secretion by microglia stimulated with LPS or amyloid-beta (Aβ), a hallmark peptide of Alzheimer’s Disease (122). In a triple transgenic mouse model of Alzheimer’s Disease, IFN-γ/TNF-α primed MSC-EVs delivered intranasally reduced microglia Iba-1 and CD68 (activation markers) expression and soma size, signifying an overall suppression of microglia activation (123).…”