Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
复制标题
抑制热休克蛋白 90 可保护髓核干细胞/祖细胞免受压迫引起的坏死性凋亡和细胞凋亡
DOI：
10.3389/fcell.2020.00685
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发表时间：
2020-08-07
影响因子：
5.5
通讯作者：
Shao, Zengwu
中科院分区：
文献类型：
--
作者：
Hu, Binwu;Zhang, Shuo;Shao, Zengwu
髓核源性干祖细胞（NPSCs）为退变椎间盘（IVD）的再生提供了新的前景。然而，随着IVD的衰老和变性，npsc的频率明显降低。过度的细胞死亡可能是npsc频率下降的主要原因，然而，确切的机制尚不清楚。因此，本研究旨在探讨压缩诱导NPSCs死亡的机制，以及热休克蛋白90 （HSP90）对NPSCs存活的影响。在这里，我们发现压缩可以触发受体相互作用蛋白激酶1 (RIPK1)/受体相互作用蛋白激酶3 (RIPK3)/混合谱系激酶结构域样蛋白（MLKL）介导的npsc坏死。此外，我们发现HSP90的表达升高参与了压缩诱导的NPSCs死亡，抑制HSP90可以通过调节RIPK1/RIPK3/MLKL的表达和活性，减轻线粒体功能障碍（线粒体膜电位损失和ATP耗竭）和氧化应激（线粒体活性氧（ROS）、细胞总ROS和丙二醛的产生），显著减轻压缩诱导的NPSCs坏死。和超氧化物歧化酶2的下调]。除坏死下垂外，抑制HSP90也可减轻npsc的压迫诱导凋亡。此外，我们发现HSP70的表达增强有助于抑制HSP90的细胞保护作用。更令人鼓舞的是，我们的研究结果表明，抑制HSP90也可以减轻体内npsc的衰竭。综上所述，RIPK1/RIPK3/ mlkl介导的necroptosis参与了压缩诱导的npsc死亡。此外，靶向HSP90同时抑制NPSCs的坏死坏死和凋亡可能是防止NPSCs死亡的有效策略，从而挽救NP组织的内源性修复能力。
Nucleus pulposus-derived stem/progenitor cells (NPSCs) provide novel prospects for the regeneration of degenerated intervertebral disc (IVD). Nevertheless, with aging and degeneration of IVD, the frequency of NPSCs markedly decreases. Excessive cell death could be the main reason for declined frequency of NPSCs, however, the exact mechanisms remain elusive. Thus, the present study was undertaken to explore the mechanisms of compression-induced NPSCs death, and the effects of heat shock protein 90 (HSP90) on NPSCs survival. Here, we found that compression could trigger receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis of NPSCs. Furthermore, we found that elevated expression of HSP90 was involved in compression-induced NPSCs death, and inhibiting HSP90 could dramatically attenuate compression-induced necroptosis of NPSCs via regulating the expression and activity of RIPK1/RIPK3/MLKL, and alleviating the mitochondrial dysfunction (mitochondrial membrane potential loss and ATP depletion) and oxidative stress [production of mitochondrial reactive oxygen species (ROS), cellular total ROS and malondialdehyde, and downregulation of superoxide dismutase 2]. Besides necroptosis, compression-induced apoptosis of NPSCs was also attenuated by HSP90 inhibition. In addition, we found that enhanced expression of HSP70 contributed to the cytoprotective effects of inhibiting HSP90. More encouragingly, our results demonstrated that inhibiting HSP90 could also mitigate the exhaustion of NPSCs in vivo. In conclusion, RIPK1/RIPK3/MLKL-mediated necroptosis participates in compression-induced NPSCs death. Furthermore, targeting HSP90 to simultaneously inhibit necroptosis and apoptosis of NPSCs might be an efficient strategy for preventing the death of NPSCs, thus rescuing the endogenous repair capacity of NP tissue.