Bone marrow mesenchymal stem cell-derived exosomal microRNA-124-3p attenuates neurological damage in spinal cord ischemia-reperfusion injury by downregulating Ern1 and promoting M2 macrophage polarization

Abstract

Background: Spinal cord ischemia-reperfusion injury (SCIRI) often leads to neurological damage and mortality. In this regard, understanding the pathology of SCIRI and preventing its development are of great clinic value. Methods: Herein, we analyzed the role of bone marrow mesenchymal stem cell (BMMSC)-derived exosomal microRNA (miR)-124-3p in SCIRI. A SCIRI rat model was established, and the expression of Ern1 and M2 macrophage polarization markers (Arg1, Ym1, and Fizz) was determined using immunohistochemistry, immunofluorescence assay, RT-qPCR, and western blot analysis. Targeting relationship between miR-124-3p and Ern1 was predicted using bioinformatic analysis and verified by dual-luciferase reporter assay. Macrophages were co-cultured with miR-124-3p-containing BMMSCderived exosomes. M2 macrophages were identified using flow cytometry, and the expression of Arg1, Ym1, and Fizz was determined. In addition, SCIRI rats were injected with miR-124-3p-containing exosomes, spinal cord cell apoptosis was observed using TUNEL assay, and the pathological condition was evaluated with H&E staining. Results: In SCIRI, Ern1 was highly expressed and M2 polarization markers were poorly expressed. Silencing Ern1 led to elevated expression of M2 polarization markers. MiR-124-3p targeted and negatively regulated Ern1. Exosomal miR-124-3p enhanced M2 polarization. Highly expressed exosomal miR-124-3p impeded cell apoptosis and attenuated SCIRIinduced tissue impairment and nerve injury. miR-124-3p from BMMSC-derived exosomes ameliorated SCIRI and its associated nerve injury through inhibiting Ern1 and promoting M2 polarization. Conclusion: In summary, exosomal miR-124-3p derived from BMMSCs attenuated nerve injury induced by SCIRI by regulating Ern1 and M2 macrophage polarization.

Neuron-derived exosomes-transmitted miR-124-3p protect traumatically injured spinal cord by suppressing the activation of neurotoxic microglia and astrocytes

“…As a result, they play an essential role in intercellular communication through the transfer of genetic material [ 26 , 27 ]. Recent studies have focused on exosomal contents, including proteins and RNAs, and attempted to determine their underlying mechanisms in the treatment of various diseases [ 25 , 28 – 31 ]. It has been shown that exosomal miRNAs can exert their regulatory effects on target cells, thus representing a new mode of intracellular communication [ 18 ].…”

Silence of Long Noncoding RNA SNHG14 Alleviates Ischemia/Reperfusion-Induced Acute Kidney Injury by Regulating miR-124-3p/MMP2 Axis

“…MiR-126 is validated to suppress oxidative stress by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) in I/R-induced renal models of mice [ 26 ]. As a widely explored miRNA, miR-124-3p has been documented to exert critical roles in I/R-caused injury [ 27 , 28 ]. Liang et al have indicated that upregulation of miR-124-3p reduces H/R-caused production of tumor necrosis factor-alpha (TNF- α ), interleukin-1 beta (IL-1 β ), and IL-6 in human cardiac myocytes [ 27 ].…”

“…Liang et al have indicated that upregulation of miR-124-3p reduces H/R-caused production of tumor necrosis factor-alpha (TNF- α ), interleukin-1 beta (IL-1 β ), and IL-6 in human cardiac myocytes [ 27 ]. Li et al have declared that increasing miR-124-3p attenuates I/R-induced nerve injury in the spinal cord [ 28 ]. Nonetheless, the modulation of miR-124-3p by SNHG14 in I/R-induced renal injury has not been clarified.…”

Mesenchymal Stem Cell-Derived Exosomes: Hope for Spinal Cord Injury Repair

“…MSC-exosomes can regulate macrophage/microglial polarization through regulation of pathways by exogenous miRNAs and long ncRNAs (lncRNAs). Endoplasmic reticulum stress is induced after SCI [102], and miR-124-3p can inhibit the expression of the endoplasmic reticulum to nucleus signaling 1, which is a major regulator of endoplasmic reticulum stress [87]. Exogenous miR-124-3p is transferred to macrophages through MSC-exosomes and enhances the polarization of M2 macrophages by inhibiting the expression of endoplasmic reticulum to nucleus signaling 1 [87].…”

“…Endoplasmic reticulum stress is induced after SCI [102], and miR-124-3p can inhibit the expression of the endoplasmic reticulum to nucleus signaling 1, which is a major regulator of endoplasmic reticulum stress [87]. Exogenous miR-124-3p is transferred to macrophages through MSC-exosomes and enhances the polarization of M2 macrophages by inhibiting the expression of endoplasmic reticulum to nucleus signaling 1 [87]. In addition, MSC-exosomes carrying miR-216a-5p activate phosphatidylinositide 3-kinases (PI3K)/serine/threonine kinase (AKT), inhibit the Toll-like receptor 4/nuclear factor kappa B (NF-kB) signaling pathways, and transform M1 microglia into M2 microglia [83].…”