β-Arrestin1 inhibits chemotherapy-induced intestinal stem cell apoptosis and mucositis.
β-Arrestin1 inhibits chemotherapy-induced intestinal stem cell apoptosis and mucositis.
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DOI：
10.1038/cddis.2016.136
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发表时间：
2016-05-19
影响因子：
9
通讯作者：
Wu B
中科院分区：
文献类型：
--
作者：
Zhan Y;Xu C;Liu Z;Yang Y;Tan S;Yang Y;Jiang J;Liu H;Chen J;Wu B
化疗引起胃肠道（GI）综合征（CIGIS）的机制仍存在争议，化疗是否会诱导肠干细胞（ISC）凋亡尚不清楚。 β-抑制蛋白是细胞凋亡、分裂和生长中 G 蛋白偶联受体信号传导的调节剂和介质。在本研究中，我们旨在探讨化疗是否会诱导 ISC 凋亡从而导致 CIGIS 粘膜炎，以及 β-arrestin1 (β-arr1) 是否参与这种凋亡。使用不同的化疗药物来生成 CIGIS 模型。 Lgr5-EGFP-IRES-creERT2+/- 敲入小鼠被用作 CIGIS 模型来研究 ISC 凋亡。使用β-arr1敲除小鼠来确定β-arr1是否参与CIGIS的细胞凋亡。进行肠组织学检查，分析ISC凋亡并检查粘膜屏障。在人类和小鼠样本以及细胞系中研究了 β-arr1 对细胞凋亡的影响。在此，我们证明化疗通过促进隐窝细胞凋亡来诱导肠粘膜炎，特别是在 Lgr5+ 干细胞和潘氏细胞中，但在杯状细胞、上皮细胞或血管内皮细胞中则不然。此外，在 CIGIS 中，β-arr1 缺陷加剧了 Lgr5+ 干细胞凋亡，但不加剧潘氏细胞凋亡。此外，数据显示β-arr1通过抑制内质网应激介导的线粒体凋亡信号传导，减少化疗诱导的Lgr5+干细胞凋亡。我们的研究表明，β-arr1 抑制化疗诱导的 ISC 凋亡，从而减轻 CIGIS 中的肠粘膜炎。
The mechanism of chemotherapy-induced gastrointestinal (GI) syndrome (CIGIS) is still controversial, and it is unclear whether chemotherapy induces intestinal stem cell (ISC) apoptosis. β-Arrestins are regulators and mediators of G protein-coupled receptor signaling in cell apoptosis, division and growth. In this study, we aimed to investigate whether chemotherapy induces ISC apoptosis to contribute to mucositis in CIGIS and whether β-arrestin1 (β-arr1) is involved in this apoptosis. Different chemotherapeutic agents were used to generate a CIGIS model. Lgr5-EGFP-IRES-creERT2+/− knock-in mice were used as a CIGIS model to investigate ISC apoptosis. β-arr1 knockout mice were used to determine whether β-arr1 is involved in the apoptosis in CIGIS. Intestinal histology was performed, the ISC apoptosis was analyzed and the mucosal barrier was examined. The effects of β-arr1 in apoptosis were investigated in the samples from humans and mice as well as in cell lines. Here, we demonstrate that chemotherapy induced intestinal mucositis by promoting crypt cell apoptosis, especially in Lgr5+ stem cells and Paneth cells but not in goblet cells, epithelial cells or vascular endothelial cells. Furthermore, β-arr1 deficiency exacerbated the Lgr5+ stem cell apoptosis, but not Paneth cell apoptosis, in CIGIS. In addition, the data showed that β-arr1 reduced the chemotherapy-induced Lgr5+ stem cell apoptosis by inhibiting endoplasmic reticulum stress-mediated mitochondrial apoptotic signaling. Our study indicates that β-arr1 inhibits chemotherapy-induced ISC apoptosis to alleviate intestinal mucositis in CIGIS.