ASIC1 and ASIC3 mediate cellular senescence of human nucleus pulposus mesenchymal stem cells during intervertebral disc degeneration.
ASIC1 and ASIC3 mediate cellular senescence of human nucleus pulposus mesenchymal stem cells during intervertebral disc degeneration.
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ASIC1和ASIC3介导椎间盘退变过程中人髓核间充质干细胞的细胞衰老
DOI：
10.18632/aging.202850
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发表时间：
2021-04-06
期刊：
影响因子：
--
通讯作者：
Shen C
中科院分区：
文献类型：
--
作者：
Ding J;Zhang R;Li H;Ji Q;Cheng X;Thorne RF;Hondermarck H;Liu X;Shen C
干细胞方法已成为治疗椎间盘退行性变(IVDD)的一种有吸引力的选择。髓核间充质干细胞(NP-MSCs)参与了椎间盘(IVD)的再生和内稳态，但调控这些过程的分子机制尚不清楚。酸敏离子通道(ASICs)是中枢和外周神经元胞外质子的关键受体，已被认为与IVDD有关，其中退变与微环境pH降低有关。在这里，我们显示ASIC1和ASIC3，而不是ASIC2和ASIC4在人类IVD中根据临床退变的程度而上调。将IVD来源的NP-MSCs置于pH 6.6的培养条件下，模拟IVD的病理变化，导致细胞增殖下降，这与细胞周期停滞和诱导衰老有关。观察到的关键分子变化是P53、p21、p27、p16和Rb1的表达增加。提示，使用ASIC抑制剂可以在很大程度上缓解NP-MSCs的早衰，这表明ASIC1和ASIC3都在上游起决定性作用，激活衰老编程通路，包括p53-p21/p27和p16-Rb1信号。这些结果突出了ASIC抑制剂作为IVDD治疗方法的潜力，并广泛定义了一个可用于评估其他IVDD疗法的体外系统。
Stem cell approaches have become an attractive therapeutic option for intervertebral disc degeneration (IVDD). Nucleus pulposus mesenchymal stem cells (NP-MSCs) participate in the regeneration and homeostasis of the intervertebral disc (IVD), but the molecular mechanisms governing these processes remain to be elucidated. Acid-sensing ion channels (ASICs) which act as key receptors for extracellular protons in central and peripheral neurons, have been implicated in IVDD where degeneration is associated with reduced microenvironmental pH. Here we show that ASIC1 and ASIC3, but not ASIC2 and ASIC4 are upregulated in human IVDs according to the degree of clinical degeneration. Subjecting IVD-derived NP-MSCs to pH 6.6 culture conditions to mimic pathological IVD changes resulted in decreased cell proliferation that was associated with cell cycle arrest and induction of senescence. Key molecular changes observed were increased expression of p53, p21, p27, p16 and Rb1. Instructively, premature senescence in NP-MSCs could be largely alleviated using ASIC inhibitors, suggesting both ASIC1 and ASIC3 act decisively upstream to activate senescence programming pathways including p53-p21/p27 and p16-Rb1 signaling. These results highlight the potential of ASIC inhibitors as a therapeutic approach for IVDD and broadly define an in vitro system that can be used to evaluate other IVDD therapies.
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酸性离子通道有助于神经毒性。
影响因子：
6.9
作者：
Chu XP;Grasing KA;Wang JQ
通讯作者：
Wang JQ
影响因子：
3
作者：
Bibby, SRS;Jones, DA;Urban, JPG
通讯作者：
Urban, JPG
影响因子：
3
作者：
Erwin, W. Mark;Islam, Diana;Fehlings, Michael G.
通讯作者：
Fehlings, Michael G.
影响因子：
15.9
作者：
Ben-Porath, I;Weinberg, RA
通讯作者：
Weinberg, RA
DOI：
10.1073/pnas.211053698
发表时间：
2001-10-09
影响因子：
11.1
作者：
Krtolica, A;Parrinello, S;Campisi, J
通讯作者：
Campisi, J