Tail-vein injection of MSC-derived small extracellular vesicles facilitates the restoration of hippocampal neuronal morphology and function in APP / PS1 mice

Abstract

Mesenchymal stem-cell-derived small extracellular vesicles (MSC-EVs), as a therapeutic agent, have shown great promise in the treatment of neurological diseases. To date, the neurorestorative effects and underlying mechanism of MSC-EVs in Alzheimer’s disease (AD) are not well known. Herein, we aimed to investigate the action of MSC-EVs on the neuronal deficits in β-amyloid protein (Aβ)-stimulated hippocampal neurons, or AD cell (SHSY5Y cell lines) and animal (APPswe / PS1dE9 mice) models. In the present study, the cell and AD models received a single-dose of MSC-EVs, and were then assessed for behavioral deficits, pathological changes, intracellular calcium transients, neuronal morphology alterations, or electrophysiological variations. Additionally, the nuclear factor E2-related factor 2 (Nrf2, a key mediator of neuronal injury in AD) signaling pathway was probed by western blotting in vitro and in vivo models of AD. Our results showed that MSC-EVs therapy improved the cognitive impairments and reduced the hippocampal Aβ aggregation and neuronal loss in AD mice. Markedly, EV treatment restored the calcium oscillations, dendritic spine alterations, action potential abnormalities, or mitochondrial changes in the hippocampus of AD models. Also, we found that the Nrf2 signaling pathway participated in the actions of MSC-EVs in the cell and animal models. Together, these data indicate that MS-EVs as promising nanotherapeutics for restoration of hippocampal neuronal morphology and function in APP / PS1 mice, further highlighting the clinical values of MSC-EVs in the treatment of AD.

Extracellular Vesicles Derived From Ex Vivo Expanded Regulatory T Cells Modulate In Vitro and In Vivo Inflammation

“…The in vivo results using Treg EVs suggest an antiinflammatory effect in a model of inflammation and a motor neuron degenerative disease model of ALS. EVs have been administered previously into preclinical animal models of disease with efficiency and effectiveness, particularly in influencing the peripheral immune system (72)(73)(74)(75)(76)(77). IV administration of the Treg EVs demonstrated a robust ability to dampen pro-inflammatory transcripts in peripheral CD11b+ myeloid cells.…”

Recommendation: Treatment of clinical long COVID encephalopathies with nasal administered mesenchymal stromal cell extracellular vesicles

“…The uptake of 18F-deoxy-glucose as an objective measure of the brain glucose metabolism, PET imaging, and cognitive function improved significantly in AD transgenic mice (Chen et al, 2021). Yet, in another study of a murine Alzheimer's model receiving intravenous MSC-EVs, there were improved cognitive impairments and reduced hippocampal Aβ aggregates and neuronal loss, restored brain electrical activities, as well as favorable mitochondrial changes (Wang et al, 2021).…”

Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease

“…Rather than studying the actual brain delivery, most studies rely on therapeutic outcomes of MSC-EV treatment in AD models instead, though some researchers also directly demonstrated EV distribution [25]. To date, MSC-EV therapy has achieved exceptional efficacy in many neurological disease models [10,11,26,27] by reducing pathological protein accumulation, alleviating neuroinflammation and oxidative stress, and protecting the nerves [28][29][30][31]. Further functionalisation of MSC-EVs has also been studied for improved therapeutic performance.…”