International journal of experimental pathologyNov 7, 2025

Bone marrow stem cell particles with miR-221-3p reduce stress-related cell death in spinal disc cells through the Nrf2/HO-1 pathway

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 6, 2026

Abstract

Exosomes from bone marrow mesenchymal stem cells significantly reduced apoptosis in nucleus pulposus cells induced by advanced glycation end products.

Excessive endoplasmic reticulum stress is linked to cell death in nucleus pulposus cells, contributing to intervertebral disc degeneration.
MiR-221-3p levels decreased in nucleus pulposus cells exposed to advanced glycation end products.
Co-culturing nucleus pulposus cells with exosomes from bone marrow mesenchymal stem cells restored miR-221-3p levels.
Treatment with bone marrow mesenchymal stem cell exosomes reversed the negative effects of advanced glycation end products on cell viability and reduced markers of apoptosis and endoplasmic reticulum stress.
Knocking down miR-221-3p negated the beneficial effects of bone marrow mesenchymal stem cell exosomes on the Nrf2/HO-1 pathway.
Nrf2 activation by the exosomes may play a crucial role in mitigating endoplasmic reticulum stress and apoptosis in nucleus pulposus cells.

Simplified

Excessive endoplasmic reticulum (ER) stress can lead to apoptosis of nucleus pulposus cells (NPCs), a hallmark of intervertebral disc degeneration (IVDD). Our study aimed to determine whether bone marrow mesenchymal stem cells (BMSCs-exos) alleviate ER stress-related NPC apoptosis through the delivery of miR-221-3p. Human NPCs were stimulated by advanced glycation end products (AGEs) for 24 h to construct a cellular model of ER stress. Exosomes were isolated from BMSCs transfected with miR-NC and miR-221-3p inhibitor and co-cultured together with AGEs in NPCs. MiR-221-3p expression in NPCs was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). The protein levels of ER stress and apoptosis markers and nuclear factor erythroid 2 p45-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway-related molecules in NPCs were measured by western blotting and immunofluorescence staining. The Nrf2 agonist tert-butylhydroquinone (TBHQ) was used to verify whether exosomal miR-221-3p affected ER stress-mediated apoptosis by regulating the Nrf2/HO-1 pathway. MiR-221-3p expression was decreased in AGEs-stimulated NPCs, while co-culture with BMSCs-exos rescued such a decline. AGEs-induced reduction in NPC viability and elevation in cell apoptosis and ER stress were overturned by BMSCs-exos treatment, whereas miR-221-3p knockdown further antagonized these effects of BMSCs-exos. MiR-221-3p knockdown reversed the enhancement of BMSCs-exos on Nrf2 and HO-1 levels and Nrf2 nuclear translocation in AGEs-induced NPCs. Importantly, TBHQ abrogated the promotion of Exos-miR-221-3p inhibitor on ER stress and apoptosis in NPCs. BMSCs-exos reduced ER stress-mediated apoptosis in NPCs by promoting the Nrf2/HO-1 pathway through delivering miR-221-3p.

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Bone marrow stem cell particles with miR-221-3p reduce stress-related cell death in spinal disc cells through the Nrf2/HO-1 pathway

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