Bone Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote Recovery Following Spinal Cord Injury via Improvement of the Integrity of the Blood-Spinal Cord Barrier

Abstract

Mesenchymal stem cell (MSC) transplantation has been shown to represent a potential treatment for traumatic spinal cord injury (SCI). However, there are several obstacles that need to be overcome before MSCs can be considered for clinical application, such as failure of MSCs to reach the spinal cord lesion core and possible tumor formation. Recent studies have suggested that MSC treatment is beneficial owing to paracrine-secreted factors. Extracellular vesicles are considered to be some of the most valuable paracrine molecules. However, the therapeutic mechanism of extracellular vesicles on spinal cord injury has not been studied clearly. Therefore, our study investigated the effect of systemic administration of extracellular vesicles on the loss of motor function after SCI and examined the potential mechanisms underlying their effects. Disruption of the blood-spinal cord barrier (BSCB) is a crucial factor that can be detrimental to motor function recovery. Pericytes are an important component of the neurovascular unit, and play a pivotal role in maintaining the structural integrity of the BSCB. Our study demonstrated that administration of bone mesenchymal stem cell-derived extracellular vesicles (BMSC-EV) reduced brain cell death, enhanced neuronal survival and regeneration, and improved motor function compared with the administration of BMSC-EV free culture media (EV-free CM). Besides, the BSCB was attenuated and pericyte coverage was significantly decreased in vivo. Furthermore, we found that exosomes reduced pericyte migration via downregulation of NF-κB p65 signaling, with a consequent decrease in the permeability of the BSCB. In summary, we identified that extracellular vesicles treatment suppressed the migration of pericytes and further improved the integrity of the BSCB via NF-κB p65 signaling in pericytes. Our data suggest that extracellular vesicles may serve as a promising treatment strategy for SCI.

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

“…A series of studies have uncovered the curative effects of human mesenchymal stem cell (hMSC)-derived EVs, for treating a variety of neurological conditions. The beneficial effects of MSC-derived EVs were observed in animal models of traumatic brain injury (TBI) [19,20], stroke or ischemia [21][22][23], status epilepticus-induced brain injury [24], multiple sclerosis [25], Alzheimer's disease (AD) [26], and spinal cord injury [27]. For example, intravenous (IV) administration of hMSC-EVs an hour after the induction of controlled cortical impact injury was efficient for suppressing the early surge of proinflammatory cytokines as well as easing TBI-induced cognitive impairments [20].…”

Underwater-treadmill training attenuates blood-spinal cord barrier disruption by promoting angiogenesis and inhibiting MMP-2/9 expression following spinal cord injury

“…The integrity of the BSCB is essential for the spinal cord to maintain normal function [31]. However, the BSCB is destroyed after SCI, which leads to increased permeability, causing a series of secondary damage [14,32]. In our study, through the horizontal comparison of data of each group in the same period, we found that the degree of edema in the M group increased signi cantly compared to that of S group.…”

“…Previous studies have mainly focused on drug treatment after SCI [14,15]. However, this often has certain side effects, affecting the quality of life of patients.…”

Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications

“…SCI is frequently associated with microvascular stability disruption and an increase in blood-spinal cord barrier (BSCB) permeability, mainly caused by abnormal migration of pericytes [60,61]. Notably, treatment with mouse BMMSC-EVs inhibited the migration of pericytes and thereby improved the structural integrity of the BSCB and, in turn, the motor function in a SCI rat model [62]. Another potent mechanism of spinal cord recovery upon BMMSC-EVs treatment suggested the prevention of neuronal apoptosis through the activation of the Wnt/β-catenin signalling pathway [63].…”