Micro electrical fields induced MSC-sEVs attenuate neuronal cell apoptosis by activating autophagy via lncRNA MALAT1/miR-22-3p/SIRT1/AMPK axis in spinal cord injury

Abstract

Spinal cord injury (SCI) is a traumatic condition of the central nervous system that causes paralysis of the limbs. Micro electric fields (EF) have been implicated in a novel therapeutic approach for nerve injury repair and regeneration, but the effects of human umbilical cord mesenchymal stem cell-derived small extracellular vesicles that are induced by micro electric fields (EF-sEVs) stimulation on SCI remain unknown. The aim of the present study was to investigate whether EF-sEVs have therapeutic effects a rat model of SCI. EF-sEVs and normally conditioned human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (CON-sEVs) were collected and injected intralesionally into SCI model rats to evaluate the therapeutic effects. We detect the expression of candidate long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA-MALAT1) in EF-sEVs and CON-sEVs. The targets and downstream effectors of lncRNA-MALAT1 were investigated using luciferase reporter assays. Using both in vivo and in vitro experiments, we demonstrated that EF-sEVs increased autophagy and decreased apoptosis after SCI, which promoted the recovery of motor function. We further confirmed that the neuroprotective effects of EF-sEVs in vitro and in vivo correlated with the presence of encapsulated lncRNA-MALAT1 in sEVs. lncRNA-MALAT1 targeted miR-22-3p via sponging, reducing miR-22-3p’s suppressive effects on its target, SIRT1, and this translated into AMPK phosphorylation and increased levels of the antiapoptotic protein Bcl-2. Collectively, the present study identified that the lncRNA-MALAT1 in EF-sEVs plays a neuroprotective role via the miRNA-22-3p/SIRT1/AMPK axis and offers a fresh perspective and a potential therapeutic approach using sEVs to improve SCI.

Research progress on long non‑coding RNAs in non‑infectious spinal diseases (Review)

“…By contrast, TSIIA reduced cell damage and increased the expression of TCTN2; follow-up experiments demonstrated that TCTN2 may act as a regulator of dual-specificity phosphatase 1 (DUSP1) expression through miR-125a-5p; that is, TSIIA may regulate SCI through the TCTN2/miR-125a-5p/DUSP1 axis ( 109 ). In another previous study ( 110 ), researchers injected small extracellular vesicles (sEVs) derived from human umbilical cord mesenchymal stem cells induced by micro-electric field stimulation (EF-sEVs) and normally conditioned human umbilical cord mesenchymal stem cells-derived sEVs. Within the lesions of rats with SCI, MALAT1 expression was elevated in tissues treated with EF-sEVs.…”

“…Within the lesions of rats with SCI, MALAT1 expression was elevated in tissues treated with EF-sEVs. In addition, a luciferase reporter gene assay showed that MALAT1 can competitively bind to miR-22-3p and reduce its inhibitory effect on SIRT1, thereby improving SCI ( 110 ). A study has indicated that photobiomodulation (PBM) reduces inflammation by inhibiting bone marrow-derived macrophages.…”