title: Epigenetic Modification of the CCL5/CCR1/ERK Axis Enhances Glioma Targeting in Dedifferentiation-Reprogrammed BMSCs.
abstract: 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.
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Wayne Yuk-Wai
authors.initials: WY
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Xiao Hu
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jie Ting
authors.initials: JT
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Sien
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Liang Liang
authors.initials: LL
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Biao
authors.initials: B
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Fu Yuan
authors.initials: FY
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Hai Long
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.affiliation: Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Willaime-Morawek
authors.affiliation: Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China; The Chinese University of Hong Kong, Shenzhen Research Institute, Shenzhen 518057 PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: 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; The Chinese University of Hong Kong, Shenzhen Research Institute, Shenzhen 518057 PR China. Electronic address: hsiaocchan@cuhk.edu.hk.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
authors.affiliation: 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; The Chinese University of Hong Kong, Shenzhen Research Institute, Shenzhen 518057 PR China. Electronic address: xjiang@cuhk.edu.hk.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D002465:Cell Movement / Q000235:genetics; D065150:Cellular Reprogramming; D018946:Chemokine CCL5 / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D054389:Receptors, CCR1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018946:Chemokine CCL5; D018925:Chemokines; D006657:Histones; D054389:Receptors, CCR1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: BMSCs; CCL5; dedifferentiation; glioma; histone modification