Bone mesenchymal stem cell-derived extracellular vesicles promote the repair of intervertebral disc degeneration by transferring microRNA-199a

Abstract

Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) protect intervertebral disc degeneration (IDD) by regulating nucleus pulposus cell (NPC) apoptosis. But the mechanism of BMSCs-EVs-microRNA (miR)-199a in IDD remains unclear. In this study, after the acquisition and identification of BMSCs and BMSCs-EVs, IDD mouse model was established and treated with BMSCs-EVs. The pathological changes of NPCs, positive expression of MMP-2, MMP-6 and TIMP1, and the senescence and apoptosis of NPCs were evaluated. Microarray analysis was employed to analyze the differentially expressed miRs and genes after EV treatment. NPCs were treated with EVs/miR-199a/TGF-β agonist SRI-011381. The positive expression of col II and Aggrecan was assessed. The target gene and downstream pathway of miR-199a were analyzed. In vivo experiment, after BMSCs-EV treatment, MMP-2, MMP-6, TIMP1 and TUNEL-positive cells in IDD mice were decreased, and miR-199a was increased. In vitro experiments, the expression of col Ⅱ and Aggrecan, SA-β gal positive cells and apoptosis rate of NPCs were decreased after EV intervention. The protective effect of BMSCs-EVs on NPCs was impaired by reducing miR-199a carried by EVs. miR-199a could target GREM1 to inactivate the TGF-β pathway. miR-199a carried by BMSCs-EVs promotes IDD repair by targeting GREM1 and downregulating the TGF-β pathway. Our work confers a promising therapeutic strategy for IDD.