Activation of Notch1 signaling alleviates dysfunction of bone marrow-derived mesenchymal stem cells induced by cigarette smoke extract.
Activation of Notch1 signaling alleviates dysfunction of bone marrow-derived mesenchymal stem cells induced by cigarette smoke extract.
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Notch1信号激活可减轻香烟烟雾提取物诱导的骨髓间充质干细胞功能障碍
DOI：
10.2147/copd.s146201
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发表时间：
2017
影响因子：
2.8
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Cheng Y;Gu W;Zhang G;Li X;Guo X
骨髓来源的间充质干细胞（BM-MSC）被认为是用于治疗COPD的有吸引力的治疗剂。但是，关于Notch对香烟烟雾（CS）微环境中MSC的增殖，迁移和存活的影响知之甚少。在这里，我们使用CS提取物在体外模仿CS微环境，目的是研究Notch在调节BM-MSC的增殖，迁移和存活中的影响。大鼠骨髓间充质干细胞被含有Notch1（N1ICD）的细胞内结构域的慢病毒载体感染，并用CS提取物进行了挑战。通过Ki67染色和与细胞周期相关蛋白的表达检测细胞增殖。使用Transwell测定法测量细胞迁移，并检查了凋亡蛋白的表达。过表达N1ICD的BM-MSC的增殖显着增加。一致地，N1ICD过表达的细胞中细胞周期蛋白D1，P-RB和E2F-1的水平升高。与对照组相比，N1ICD的过表达也增加了细胞迁移。 N1ICD的过表达平衡了Bax和Bcl-2的表达，并阻塞了caspase-3裂解，从而有助于抑制细胞凋亡。此外，PI3K/AKT途径的封锁抑制了N1ICD的上述细胞保护作用。总之，Notch信号传导的激活改善了BM-MSC在CS微环境中部分通过PI3K/AKT途径的增殖，迁移和存活。
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are considered attractive therapeutic agents for the treatment of COPD. However, little is known about the impact of Notch on the proliferation, migration, and survival of MSCs in a cigarette smoke (CS) microenvironment. Here, we used CS extract to mimic the CS microenvironment in vitro, with the intention to investigate the effect of Notch in regulating proliferation, migration, and survival of BM-MSCs. Rat bone marrow mesenchymal stem cells were infected with lentivirus vector containing the intracellular domain of Notch1 (N1ICD) and challenged with CS extract. Cell proliferation was detected by Ki67 staining and expression of cell cycle-related proteins. A transwell assay was used to measure cell migration and the expression of apoptotic proteins was examined. The proliferation of BM-MSCs overexpressing N1ICD significantly increased. Consistently, levels of cyclin D1, p-Rb, and E2F-1 increased in N1ICD overexpressing cells. N1ICD overexpression also increased cell migration compared with the control group. N1ICD overexpression equilibrated the expression of Bax and Bcl-2, and blocked caspase-3 cleavage, contributing to the inhibition of apoptosis. Moreover, blockade of the PI3K/Akt pathway suppressed the aforementioned cytoprotective effects of N1ICD. In conclusion, activation of Notch signaling improved proliferation, migration, and survival of BM-MSCs in a CS microenvironment partly through the PI3K/Akt pathway.