Chen Rui, Lee Wayne Yuk-Wai, Zhang Xiao Hu, Zhang Jie Ting, Lin Sien, Xu Liang Liang, Huang Biao, Yang Fu Yuan, Liu Hai Long, Wang Bin, Tsang Lai Ling, Willaime-Morawek Sandrine, Li Gang, Chan Hsiao Chang, Jiang Xiaohua
Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China; Epithelial Cell Biology Research Center, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
Stem Cell Reports. 2017 Mar 14;8(3):743-757. doi: 10.1016/j.stemcr.2017.01.016. Epub 2017 Feb 16.
The success of stem cell-mediated gene therapy in cancer treatment largely depends on the specific homing ability of stem cells. We have previously demonstrated that after in vitro induction of neuronal differentiation and dedifferentiation, bone marrow stromal cells (BMSCs) revert to a primitive stem cell population (De-neu-BMSCs) distinct from naive BMSCs. We report here that De-neu-BMSCs express significantly higher levels of chemokines, and display enhanced homing abilities to glioma, the effect of which is mediated by the activated CCL5/CCR1/ERK axis. Intriguingly, we find that the activated chemokine axis in De-neu-BMSCs is epigenetically regulated by histone modifications. On the therapeutic front, we show that De-neu-BMSCs elicit stronger homing and glioma-killing effects together with cytosine deaminase/5-fluorocytosine compared with unmanipulated BMSCs in vivo. Altogether, the current study provides an insight into chemokine regulation in BMSCs, which may have more profound effects on BMSC function and their application in regenerative medicine and cancer targeting.
干细胞介导的基因疗法在癌症治疗中的成功很大程度上取决于干细胞的特异性归巢能力。我们之前已经证明，在体外诱导神经元分化和去分化后，骨髓基质细胞（BMSC）会恢复为与原始BMSC不同的原始干细胞群体（去神经化BMSC，De-neu-BMSC）。我们在此报告，De-neu-BMSC表达显著更高水平的趋化因子，并表现出对胶质瘤增强的归巢能力，其作用由激活的CCL5/CCR1/ERK轴介导。有趣的是，我们发现De-neu-BMSC中激活的趋化因子轴受组蛋白修饰的表观遗传调控。在治疗方面，我们表明，与未处理的BMSC相比，De-neu-BMSC在体内与胞嘧啶脱氨酶/5-氟胞嘧啶一起引发更强的归巢和胶质瘤杀伤作用。总之，当前的研究为BMSC中的趋化因子调节提供了见解，这可能对BMSC功能及其在再生医学和癌症靶向中的应用产生更深远的影响。
