Systemic Administration of Exosomes Released from Mesenchymal Stromal Cells Attenuates Apoptosis, Inflammation, and Promotes Angiogenesis after Spinal Cord Injury in Rats

Abstract

Spinal cord injury (SCI) is one of the most common devastating injuries, which causes permanent disabilities such as paralysis and loss of movement or sensation. The precise pathogenic mechanisms of the disease remain unclear, and, as of yet, there is no effective cure. Mesenchymal stem cells (MSCs) show promise as an effective therapy in the experimental models of SCI. MSCs secrete various factors that can modulate a hostile environment, which is called the paracrine effect. Among these paracrine molecules, exosome is considered to be the most valuable therapeutic factor. Thus, exosomes from MSCs (MSCs-exosomes) can be a potential candidate of therapeutic effects of stem cells. The present study was designed to investigate the effect of whether systemic administration of exosomes generated from MSCs can promote the function recovery on the rat model of SCI in vivo. In the present study, we observed that systemic administration of MSCs-exosomes significantly attenuated lesion size and improved functional recovery post-SCI. Additionally, MSCs-exosomes treatment attenuated cellular apoptosis and inflammation in the injured spinal cord. Expression levels of proapoptotic protein (Bcl-2-associated X protein) and proinflammatory cytokines (tumor necrosis factor alpha and interleukin [IL]-1β) were significantly decreased after MSCs-exosomes treatment, whereas expression levels of antiapoptotic (B-cell lymphoma 2) and anti-inflammatory (IL-10) proteins were upregulated. Further, administration of MSCs-exosomes significantly promoted angiogenesis. These results show, for the first time, that systemic administration of MSCs-exosomes attenuated cell apoptosis and inflammation, promoted angiogenesis, and promoted functional recovery post-SCI, suggesting that MSCs-exosomes hold promise as a novel therapeutic strategy for treating SCI.

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

“…Compared with factors in the absence of membrane packaging, exosomes are more stable and capable of targeting inflammatory sites due to their enhanced permeability and retention effects [62,63]. MSC-exo have been confirmed to exert beneficial effects on functional recovery and suppress the activation of A1 neurotoxic reactive astrocytes after SCI [24,64]; However, it remains unclear whether these effects are comparable to those of live MSCs when applied systemically to SCI rats. In addition, the underlying mechanisms of Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry the A1-inhibitory effects exerted by MSC-exo have not been investigated before.…”

“…Moreover the therapeutic effects of cell-free exosomes are comparable with those of intact MSCs after brain injury [16,17,23]. A previous study of applications of MSC-exo to an SCI model suggesting that systemic administration reduced levels of proinflammatory cytokines and improved function recovery [24]; however, the precise mechanisms associated with the beneficial effects on SCI remain unknown. Based on the reported anti-inflammatory effects, we hypothesized that both MSC and MSC-exo might play an inhibitory role on inflammationinduced A1 astrocytes.…”

Inhalation of Hydrogen of Different Concentrations Ameliorates Spinal Cord Injury in Mice by Protecting Spinal Cord Neurons from Apoptosis, Oxidative Injury and Mitochondrial Structure Damages

“…Apoptosis is primarily regulated by the upstream Bcl-2 family and the downstream caspase family, among which anti-apoptotic (Bcl-2) or pro-apoptotic (Bax) molecules are the most common markers of programmed cell death [41, 43]. In this study, we demonstrated that 75% hydrogen incubation prevented neuronal apoptosis.…”

“…The SCI procedure is related to complicated pathophysiological mechanisms, among which apoptosis is the major event of secondary injury after SCI [41, 42]. Apoptosis is primarily regulated by the upstream Bcl-2 family and the downstream caspase family, among which anti-apoptotic (Bcl-2) or pro-apoptotic (Bax) molecules are the most common markers of programmed cell death [41, 43].…”

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…Although all exosomes contain the constitutive array of proteins, lipids, and RNAs, their contents vary in accordance with the cellular origin and the physiological or pathological condition of the cell and of its extracellular environment [204]. Most of the studies have demonstrated that MSC-derived exosomes contain various miRNAs, which participate in the cell-cell communication and alter the fate of recipient cells [204,223,224].…”