Mesenchymal stem cells attenuate doxorubicin-induced cellular senescence through the VEGF/Notch/TGF-β signaling pathway in H9c2 cardiomyocytes
Mesenchymal stem cells attenuate doxorubicin-induced cellular senescence through the VEGF/Notch/TGF-β signaling pathway in H9c2 cardiomyocytes
复制标题
间充质干细胞通过 H9c2 心肌细胞中的 VEGF/Notch/TGFbeta 信号通路减轻阿霉素诱导的细胞衰老。
DOI：
10.3892/ijmm.2018.3635
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发表时间：
2018-07-01
影响因子：
5.4
通讯作者：
Hou, Meng
中科院分区：
文献类型：
--
作者：
Chen, Lingli;Xia, Wenzheng;Hou, Meng
阿霉素（Dox）的心脏毒性限制了其临床应用。它引起的基本变化包括间质心肌纤维化和衰老心肌细胞的出现。据报道，基于间充质干细胞（MSC）的疗法也可调节细胞衰老，并已有效用于治疗与年龄相关的心血管疾病。本研究采用Transwell细胞培养系统将H9 c2细胞与MSCs共培养，观察H9 c2细胞的增殖和存活情况。逆转录-定量聚合酶链反应检测衰老相关基因p53、p16的表达及端粒长度，Western blot检测Jagged-1/Notch-1信号通路。结果显示，Dox诱导H9 c2细胞衰老，其特征在于增殖率低，活力差，端粒长度减少，端粒酶活性受损，p53和p16表达显著增加。与此相反，当在Dox存在下与MSC共培养时，H9 c2细胞增殖和活力增加，而p53和p16的表达水平降低，端粒长度和端粒酶活性增加。阐明了MSCs抗衰老作用的机制，其机制涉及血管内皮生长因子（VEGF）/Jagged-1/Notch-1/转化生长因子-β 1（TGF-β 1）信号通路。证实抑制VEGF、或用小干扰RNA沉默Jagged-1或Notch-1、或使用重组TGF-β 1消除MSC对Dox处理的H9 c2细胞的抗衰老作用。结果显示，MSC通过释放VEGF，激活Jagged-1/Notch-1信号通路，从而抑制TGF-β 1的释放，拯救H9 c2细胞免于Dox诱导的衰老。因此，用MSC治疗可能对用Dox治疗的癌症患者的心脏毒性的衰减具有重要的治疗意义。
The clinical use of doxorubicin (Dox) is limited by its cardiotoxicity. The fundamental changes it induces include interstitial myocardial fibrosis and the appearance of senescent cardiomyocytes. Mesenchymal stem cell (MSC)-based therapies have also been reported to modulate cellular senescence, and have been used effectively to treat age-related cardiovascular diseases. In the present study, the Transwell system was used to coculture H9c2 cells with MSCs, and their proliferation and viability were assessed. The expression of senescence-related genes p53 and p16, and telomere length were measured using reverse transcription-quantitative polymerase chain reaction analysis, and the Jagged-1/Notch-1 signaling pathway was detected using western blot analysis. The results revealed that Dox induced the senescence of H9c2 cells, characterized by a low proliferation rate, poor viability, reduced telomere length and impaired telomerase activity, and by marked increases in the expression of p53 and p16. By contrast, when cocultured with MSCs in the presence of Dox, H9c2 cell proliferation and viability increased, whereas the expression levels of p53 and p16 decreased, and telomere length and telomerase activity increased. The mechanism underlying the antisenescence function of MSCs was clarified, which involved the vascular endothelial growth factor (VEGF)/Jagged-1/Notch-1/transforming growth factor-beta 1 (TGF-beta 1) signaling pathway. It was confirmed that inhibiting VEGF, or silencing Jagged-1 or Notch-1 with small interfering RNA, or using recombinant TGF-beta 1 eliminated the antisenescence effects of MSCs on the Dox-treated H9c2 cells. The results revealed that MSCs rescued H9c2 cells from Dox-induced senescence through the release of VEGF, which activated the Jagged-1/Notch-1 signaling pathway, leading to the inhibition of TGF-beta 1 release. Therefore, treatment with MSCs may have important therapeutic implications on the attenuation of cardiotoxicity in patients with cancer treated with Dox.