Epigenetic Modification of the CCL5/CCR1/ERK Axis Enhances Glioma Targeting in Dedifferentiation-Reprogrammed BMSCs

• Published in: Stem cell reports 2017-03, Vol.8 (3), p.743-757
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; BMSCs; CCL5; Cell Dedifferentiation; Cell Movement - genetics; Cellular Reprogramming; Chemokine CCL5 - metabolism; Chemokines - metabolism; dedifferentiation; Epigenesis, Genetic; Extracellular Signal-Regulated MAP Kinases - metabolism; glioma; Glioma - genetics; Glioma - metabolism; histone modification; Histones - metabolism; Humans; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mice; Receptors, CCR1 - metabolism; Signal Transduction
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.01.016

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. [Display omitted] •Dedifferentiation-mediated reprogramming enhances the migratory ability of BMSCs•CCL5/CCR1/ERK signaling is essential for enhanced migratory ability in De-neu-BMSCs•De-neu-BMSCs chemokine expression is epigenetically regulated by histone modification•De-neu-BMSCs elicit stronger glioma-killing effects together with suicide gene In this article, Jiang, Chan, and colleagues show that an in vitro culture strategy through neuronal differentiation and dedifferentiation can reprogram BMSCs with enhanced migratory capacity and homing ability toward cancer, the effect of which is mediated by the H4ac/CCL5/CCR1/ERK pathway.