Leukemia-derived exosomes induced IL-8 production in bone marrow stromal cells to protect the leukemia cells against chemotherapy
Leukemia-derived exosomes induced IL-8 production in bone marrow stromal cells to protect the leukemia cells against chemotherapy
复制标题
白血病来源的外泌体诱导骨髓基质细胞产生 IL-8，以保护白血病细胞免受化疗的影响。
DOI：
10.1016/j.lfs.2019.02.003
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发表时间：
2019-03-15
期刊：
影响因子：
6.1
通讯作者：
Dong, Min
中科院分区：
文献类型：
--
作者：
Chen, Tongtong;Zhang, Guozhen;Dong, Min
目的：骨髓基质细胞（BMSCs）与急性髓性白血病（AML）细胞之间的相互作用通过分泌生长因子、细胞因子和细胞外囊泡在AML耐药中起关键作用。Exosomes作为一种细胞外囊泡，由蛋白质和RNA组成，调节细胞间的通讯。主要方法：将骨髓间充质干细胞、HS 5细胞和AML细胞与transwell膜共培养，用不同剂量的AML化疗药物依托泊苷处理。我们的研究结果证明，骨髓间充质干细胞与AML细胞的共培养可以保护AML免受依托泊苷引发的细胞死亡，而不影响细胞生长。在条件培养基中共培养的BMSC和AML的外泌体中观察到70 kDa热休克蛋白（HSP 70）以及溶酶体相关膜蛋白3（CD 63）的表达增加。BMSC和AML共培养系统中的外泌体抑制重建了KG 1A细胞对依托泊苷触发的凋亡的敏感性，表明外泌体调节AML的耐药性。我们的研究证明，来源于KG 1A细胞的exosomes可以促进BMSCs产生IL-8，从而调节足叶乙甙的作用。此外，IL-8抗体的抑制作用增加了AML细胞对依托泊苷诱导的细胞死亡的敏感性，提示AML细胞分泌的exosomes是骨髓间充质干细胞与AML细胞相互作用的重要通讯者，它可以保护AML细胞免受化疗药物诱导的细胞凋亡。
Aims: The interplay between bone marrow stromal cells (BMSCs) and acute myeloid leukemia (AML) cells plays a critical role in AML drug resistance by secreting growth factors, cytokines, and extracellular vesicles. As kind of extracellular vesicles, exosomes consist of proteins and RNAs and regulate communication among cells.Main methods: The BMSCs, HS5 cells, and AML cells were co-cultivated with transwell membranes, and treated with different doses of AML chemotherapy drug, etoposide.Key findings: Findings of our research proved that co-cultivation of BMSCs with AML cells defended AML against cell death triggered via etoposide, without having an impact on cell growth. An increase in the expression of the 70 kDa heat shock proteins (HSP70) as well as lysosomal associated membrane protein 3 (CD63) was observed in the exosomes from BMSC and AML, co-cultivated in conditioned media. Exosome repression in BMSC and AML co-cultivating system rebuilt the sensitivity of the KG1A cells to apoptosis triggered via etoposide, indicating that exosome modulated drug resistance in AML. Our study proved that exosomes arising from KG1A cells could propel BMSCs to generate IL-8, which could regulate the effect of etoposide treatment. Furthermore, IL-8 inhibition by its antibody increased the sensitivity of AML cells to cell death triggered via etoposide.Significance: Our results suggested that exosomes secreted by AML cells is an essential communicator for the interaction of BMSCs and AML, which can protect AML cells from chemotherapy drug induced apoptosis.