Apoptotic extracellular vesicles derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by enhancing cell activity and regulating immunity microenvironment.
椎间盘退变（IVDD）以髓核细胞（NPCs）衰老和凋亡、细胞外基质（ECM）代谢失衡及局部慢性炎症为特征，是临床治疗中长期面临的难题。近年研究证实，移植的干细胞在体内易发生凋亡，其产生的凋亡细胞外囊泡（ApoEVs）是组织修复的关键介质。鉴于间充质干细胞（MSCs）的生理状态与IVDD微环境均具有缺氧和炎症特征，本研究探讨了经缺氧-炎症复合微环境预处理的MSCs来源凋亡小体（I-ApoEVs）对IVDD的治疗效果及机制。结果表明，与常规缺氧条件下的ApoEVs相比，I-ApoEVs能更显著地抑制NPCs衰老并促进ECM合成。更重要的是，其可靶向调控STAT6信号通路，诱导巨噬细胞向M2抗炎表型极化，从而重塑椎间盘局部炎症微环境，减轻炎症介导的退变损伤。综上所述，缺氧-炎症复合微环境预处理通过调控巨噬细胞极化增强了ApoEVs的治疗功能，为IVDD提供了一种新型且具有高度转化前景的治疗策略。
Intervertebral disc degeneration (IVDD) is characterized by the senescence and apoptosis of nucleus pulposus cells (NPCs), metabolic imbalance of the extracellular matrix (ECM), and local chronic inflammation, presenting a long-standing challenge in clinical treatment. Recent studies have confirmed that transplanted stem cells are prone to apoptosis in vivo, and the apoptotic extracellular vesicles (ApoEVs) they produce are key mediators of tissue repair. Given that both the physiological state of mesenchymal stem cells (MSCs) and the IVDD microenvironment exhibit hypoxic and inflammatory features, this study investigated the therapeutic effect and mechanism of MSCs-derived apoptotic bodies (I-ApoEVs) pretreated with a hypoxic-inflammatory composite microenvironment on IVDD. The results showed that compared with ApoEVs under conventional hypoxic conditions, I-ApoEVs more significantly inhibited NPCs senescence and promoted ECM synthesis. More importantly, they could target and regulate the STAT6 signaling pathway, induce macrophages to polarize towards the M2 anti-inflammatory phenotype, thereby remodeling the local inflammatory microenvironment of the intervertebral disc and alleviating inflammation-mediated degenerative damage. In conclusion, pretreatment with a hypoxic-inflammatory composite microenvironment enhances the therapeutic function of ApoEVs by regulating macrophage polarization, providing a novel and highly translatable therapeutic strategy for IVDD.
Weiqi Zhang, Xiaowei Ma, Han Yin, Dazhuang Miao, Tianhao Guo, Wei Chen, et al. Apoptotic extracellular vesicles derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by enhancing cell activity and regulating immunity microenvironment.. Materials today. Bio. 2026; doi:10.1016/j.mtbio.2026.103013.
Weiqi Zhang, Xiaowei Ma, Han Yin, Dazhuang Miao, Tianhao Guo, Wei Chen, et al (2026). Apoptotic extracellular vesicles derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by enhancing cell activity and regulating immunity microenvironment.. Materials today. Bio. https://doi.org/10.1016/j.mtbio.2026.103013
Weiqi Zhang, Xiaowei Ma, Han Yin, Dazhuang Miao, Tianhao Guo, Wei Chen, et al. Apoptotic extracellular vesicles derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by enhancing cell activity and regulating immunity microenvironment.[J]. Materials today. Bio, 2026 doi:10.1016/j.mtbio.2026.103013.
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