Mesenchymal-Stem-Cell–Derived Extracellular Vesicles Mitigate Trained Immunity in the Brain

Abstract

Trained immunity was recently discovered in innate immune cells and shown to facilitate the clearance of pathogens at the time of occurrence of the second insult. However, it exacerbates several aspects of neuropathologies, and proper therapy is needed to rectify this abnormal immune reaction. Mesenchymal-stem cells (MSCs) exhibit a distinct capability for brain repair but are associated with safety concerns. Extracellular vesicles derived from MSCs are a promising alternative therapy. In this study, we used lipopolysaccharides to activate trained immunity in the brain and examined the therapeutic potential of MSC-derived extracellular vesicles in mitigating the trained-immunity-induced exacerbated neuropathology. We found that MSC-derived extracellular vesicles showed comparable effects to those of MSCs in the mitigation of trained immunity in the brain. Moreover, the administration of MCS-derived extracellular vesicles mitigated the aggregated inflammatory responses in the acute stage of stroke and alleviated the trained-immunity-induced increased load of amyloid-β in APP/PS1 mice. We further investigated the molecular machinery of MSC-derived extracellular vesicles and found that IL-10 is important for the mediation of the therapeutic potential of MSC-derived extracellular vesicles toward the alleviation of trained immunity. Our study indicates that extracellular-vesicle-based regenerative strategies might be useful to mitigate trained immunity in the brain.

LSD induces increased signalling entropy in rats’ prefrontal cortex

“…In particular, Mesenchymal stem cells (MSCs) are stem cells found in many adult tissues, including brain, (Appaix, 2014) and can differentiate into neurons (Pavlova et al, 2012;Zeng et al, 2015;Zhao et al, 2015) and glial cells (George et al, 2019) to replace damaged tissues (Dimarino et al, 2013), and thus promoting neuroprotection, regeneration and repair (Qu et al, 2008;Thomi et al, 2019). They have immunomodulatory properties, mitigating the inflammation related to stroke or neurological diseases (Feng et al, 2020;Liu et al, 2019;Salari et al, 2020). Interestingly, both mesenchyme-and immune-related modules display similar topological restructuring.…”

News about Therapies of Alzheimer’s Disease: Extracellular Vesicles from Stem Cells Exhibit Advantages Compared to Other Treatments

“…In many cases, the recovery induced by low doses of MSC-EVs has been shown to start with activation of few receptors, followed by phosphorylation of kinases and various factors, and by activation of miRNAs [ 56 , 57 , 58 , 59 ]. Analogously, MSC-EVs have been shown to mitigate trained immune responses induced by innate cells, with distinct local repair [ 60 ]. In addition to the effects on neurons, MSC-EVs modulate their responses and suppress aggressive effects induced by glial cells, both astrocytes and microglia [ 61 , 62 ].…”

Biomimic Trained Immunity‐MSCs Delivery Microcarriers for Acute Liver Failure Regeneration

“…[6,[15][16][17] In this aspect, as an initial inflammatory stimulus, LPS exist in the MSCs' adaptive immune system and can trigger immune memory effects. [18][19][20][21] These LPS-activated MSCs could response in a more sustainable and efficient manner when tissue inflammatory strikes occurred. [22][23][24] In contrast, porous microcarriers have displayed broad potential not only in drug delivery, but also in cell capture and transfer.…”