Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma
Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma
复制标题
趋化因子 CCL15 介导人骨髓来源的间充质干细胞向肝细胞癌的迁移
DOI：
10.1002/stem.2275
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发表时间：
2016-04-01
期刊：
影响因子：
5.2
通讯作者：
Wang, Xuehao
中科院分区：
文献类型：
--
作者：
Gao, Yun;Zhou, Zhong;Wang, Xuehao
骨髓间充质干细胞（Mesenchymal stem cells，MSCs）具有向肿瘤部位迁移的能力，被认为是肿瘤治疗的基因载体。然而，介导这种向性的因素尚未完全阐明。在这项研究中，通过细胞因子阵列分析，发现趋化因子CCL 15是最丰富的蛋白质差异表达的肝细胞癌（HCC）细胞系相比，正常肝细胞系。酶联免疫吸附试验测定的肝癌患者血清CCL 15水平与健康对照组相比显著升高。免疫组化结果显示，CCL 15在肝癌组织中的表达明显强于癌旁组织。Transwell迁移实验表明，CCL 15可能参与体外人MSC（hMSC）向肝癌的趋化作用，并且CCL 15的这种趋化作用是通过hMSC上的CCR 1受体介导的。建立原位肝癌动物模型，研究CCL 15在hMSCs向肝癌迁移中的作用。组织学和流式细胞术分析均显示，静脉内递送后，与97 H-绿色荧光蛋白异种移植物相比，97 H-CCL 15-shRNA异种移植物中定位的hMSCs显著较少。最后，还评估了hMSCs对HCC肿瘤生长的可能影响。体外共培养实验表明hMSCs对肝癌细胞的增殖无明显影响，体内实验表明hMSCs的全身给药对肝癌细胞的生长无明显影响。本研究的结果有助于阐明hMSCs向肝癌归巢的机制。干细胞2016;34：1112-1122
Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC. Stem Cells2016;34:1112-1122