Prophylactic treatment with MSC-derived exosomes attenuates traumatic acute lung injury in rats

Abstract

The mesenchymal stem cell (MSC) is a potential strategy in the pretreatment of traumatic acute lung injury (ALI), a disease that causes inflammation and oxidative stress. This study aimed to investigate whether MSC-exosomal microRNA-124-3p (miR-124-3p) affects traumatic ALI. Initially, a traumatic ALI rat model was established using the weight-drop method. Then, exosomes were obtained from MSCs of Sprague-Dawley rats, which were injected into the traumatic ALI rats. We found that miR-124-3p was abundantly-expressed in MSCs-derived exosomes and could directly target purinergic receptor P2X ligand-gated ion channel 7 (P2X7), which was overexpressed in traumatic ALI rats. After that, a loss- and gain-of-function study was performed in MSCs and traumatic ALI rats to investigate the role of miR-124-3p and P2X7 in traumatic ALI. MSC-derived exosomal miR-124-3p or silenced P2X7 was observed to increase the survival rate of traumatic ALI rats and enhance the glutathione/superoxide dismutase activity in their lung tissues. However, the wet/dry weight of lung tissues, activity of methylenedioxyamphetamine and H2O2, and levels of inflammatory factors (TNF-a, IL-6, and IL-8) were reduced. Similarly, the numbers of total cells, macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid were also reduced when treated with exosomal miR-124-3p or silenced P2X7. In conclusion, the results provide evidence that miR-124-3p transferred by MSC-derived exosomes inhibited P2X7 expression, thus improving oxidative stress injury and suppressing inflammatory response in traumatic ALI, highlighting a potential pretreatment for traumatic ALI.

Lipopolysaccharide Inhibits Alpha Epithelial Sodium Channel Expression via MiR-124-5p in Alveolar Type 2 Epithelial Cells

“…MSCs have been a potential strategy in the pretreatment of pulmonary diseases and MSCs-CM may be a preferable therapeutic option for ALI [37]. MiR-124-3p transferred by MSCs-derived exosomes had been demonstrated to inhibit purinergic receptor P2X ligand-gated ion channel 7P2X7 expression, thus improving oxidative stress injury and suppressing inflammatory response in traumatic ALI [38,39]. In our experiment, we focused on miR-124-5p and found the inhibition of miR-124-5p on α-ENaC by binding the 3′-UTR.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration

“…The other two studies investigated the functions of the MSC-EV contents. One study showed that EV trafficking of miR-124-3p directly targeted purinergic receptor P2X ligand-gated ion channel 7 to exert anti-inflammatory effects to protect the lungs in a trauma-induced acute lung injury (ALI) model 63 .…”

Extracellular Vesicles in ARDS: New Insights into Pathogenesis with Novel Clinical Applications

“…Prophylactic treatment with mesenchymal stromal cell extracellular vesicles increased survival in rats undergoing traumatic lung injury; inflammatory cytokines, infiltrating leukocytes, and pulmonary edema were all reduced [34]. These effects were in part due to mesenchymal stromal cell extracellular vesicle transfer of miR-124 [34]. In a pig model of influenza-induced lung injury, administration of mesenchymal stromal cell extracellular vesicles similarly reduced lung injury, alveolar protein permeability, and inflammatory cytokine release.…”

“…Mesenchymal stromal cell-derived extracellular vesicles isolated from conditioned media attenuated inflammation and lung injury in both intratracheal-LPS and E. coli pneumonia models of murine lung injury [32,33]. Prophylactic treatment with mesenchymal stromal cell extracellular vesicles increased survival in rats undergoing traumatic lung injury; inflammatory cytokines, infiltrating leukocytes, and pulmonary edema were all reduced [34]. These effects were in part due to mesenchymal stromal cell extracellular vesicle transfer of miR-124 [34].…”