miR-1275 Delivered via Mesenchymal Stem Cell-Derived Extracellular Vesicles Regulates ER-Phagy Through AXIN2 in Nucleus Pulposus Cells.

Abstract

Intervertebral disc degeneration (IDD) is a major contributor to low back pain, a prevalent and debilitating condition. Nucleus pulposus (NP) cells are essential for maintaining disc homeostasis, and their dysfunction plays a crucial role in IDD development. This study aimed to explore the potential role of miR-1275, delivered via mesenchymal stem cell-derived extracellular vesicles (MSCs-EVs), in IDD pathogenesis and to elucidate the underlying molecular mechanisms through in vitro investigations. Decreased miR-1275 expression and elevated endoplasmic reticulum (ER) stress were observed in degenerated human NP tissues compared to normal controls. An in vitro IDD model was established by treating NP cells (NPCs) with advanced glycation end products (AGEs). Subsequent experiments demonstrated that EVs from miR-1275-overexpressing MSCs reduced AGE-induced ER stress, extracellular matrix (ECM) degradation, and apoptosis in NPCs by enhancing ER-phagy. Bioinformatic analyses identified AXIN2 as a direct target of miR-1275. Remarkably, AXIN2 overexpression significantly attenuated the effects of miR-1275 on NPC proliferation, apoptosis, ER stress, and ER-phagy under AGE-induced conditions. Mechanistic studies validated AXIN2 as a target of miR-1275, with miR-1275 binding to the 3' untranslated region of AXIN2 and regulating its expression. Collectively, our in vitro findings reveal that MSCs-EVs carrying miR-1275 can modulate ER stress and enhance ER-phagy in NPCs through the targeted downregulation of AXIN2, suggesting a potential molecular mechanism in IDD pathogenesis.