Li Xunlin, Wu Aimin, Han Chen, Chen Chen, Zhou Tangjun, Zhang Kai, Yang Xiao, Chen Zhiqian, Qin An, Tian Haijun, Zhao Jie
Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China.
Department of Spine Surgery, Zhejiang Spine Surgery Centre, Orthopaedic Hospital, The Second Affiliated Hospital and Yuying Children's Hospital of the Wenzhou Medical University, The Second School of Medicine Wenzhou Medical University, The Key Orthopaedic Laboratory of Zhejiang Province, Wenzhou, P. R. China.
Aging (Albany NY). 2019 Oct 30;11(20):9167-9187. doi: 10.18632/aging.102390.
Intervertebral disc degeneration (IDD) is an irreversible aging-associated clinical condition of unclear etiology. Mesenchymal stem cells (MSCs) have the potential to delay IDD, but the mechanisms by which MSCs attenuate senescence-related degeneration of nucleus pulposus cells (NPCs) remain uncertain. The present study employed a three-dimensional (3D) co-culture system to explore the influence of MSCs on NPC degeneration induced by TNF-α in rat cells. We found that co-culture with bone marrow-derived MSCs (BMSCs) reduced senescence-associated β-galactosidase expression, increased cell proliferation, decreased matrix metalloproteinase 9, increased Coll-IIa production, and reduced TGFβ/NF-κB signaling in senescent NPCs. In addition, expression of zinc metallopeptidase STE24 (ZMPSTE24), whose dysfunction is related to premature cell senescence and aging, was decreased in senescent NPCs but restored upon BMSC co-culture. Accordingly, ZMPSTE24 overexpression in NPCs inhibited the pro-senescence effects of TGFβ/NF-κB activation upon TNF-α stimulation, while both CRISPR/Cas9-mediated silencing and pharmacological ZMPSTE24 inhibition prevented those effects. Ex-vivo experiments on NP explants provided supporting evidence for the protective effect of MSCs against NPC senescence and IDD. Although further molecular studies are necessary, our results suggest that MSCs may attenuate or prevent NP fibrosis and restore the viability and functional status of NPCs through upregulation of ZMPSTE24.
椎间盘退变（IDD）是一种病因不明的与衰老相关的不可逆临床病症。间充质干细胞（MSCs）具有延缓IDD的潜力，但MSCs减轻髓核细胞（NPCs）衰老相关退变的机制仍不明确。本研究采用三维（3D）共培养系统，探讨MSCs对大鼠细胞中TNF-α诱导的NPC退变的影响。我们发现，与骨髓来源的MSCs（BMSCs）共培养可降低衰老相关β-半乳糖苷酶表达，增加细胞增殖，减少基质金属蛋白酶9，增加Ⅱ型胶原蛋白生成，并降低衰老NPCs中的TGFβ/NF-κB信号传导。此外，锌金属肽酶STE24（ZMPSTE24）的表达在衰老NPCs中降低，其功能障碍与细胞早衰和衰老有关，但在与BMSCs共培养后恢复。因此，NPCs中ZMPSTE24的过表达抑制了TNF-α刺激后TGFβ/NF-κB激活的促衰老作用，而CRISPR/Cas9介导的沉默和ZMPSTE24的药理学抑制均阻止了这些作用。对NP外植体的体外实验为MSCs对NPC衰老和IDD的保护作用提供了支持性证据。尽管还需要进一步的分子研究，但我们的结果表明，MSCs可能通过上调ZMPSTE24来减轻或预防NP纤维化，并恢复NPCs的活力和功能状态。
