title: Human Adipose Tissue-Derived Mesenchymal Stem Cells Target Brain Tumor-Initiating Cells.
abstract: In neuro-oncology, the biology of neural stem cells (NSCs) has been pursued in two ways: as tumor-initiating cells (TICs) and as a potential cell-based vehicle for gene therapy. NSCs as well as mesenchymal stem cells (MSCs) have been reported to possess tumor tropism capacities. However, there is little data on the migratory capacity of MSCs toward brain tumor-initiating cells (BTICs). This study focuses on the ability of human adipose tissue derived MSCs (hAT-MSCs) to target BTICs and their crosstalk in the microenvironment. BTICs were isolated from three different types of brain tumors. The migration capacities of hAT-MSCs toward BTICs were examined using an in vitro migration assay and in vivo bioluminescence imaging analysis. To investigate the crosstalk between hAT-MSCs and BTICs, we analyzed the mRNA expression patterns of cyto-chemokine receptors by RT-qPCR and the protein level of their ligands in co-cultured medium. The candidate cyto-chemokine receptors were selectively inhibited using siRNAs. Both in vitro and in vivo experiments showed that hAT-MSCs possess migratory abilities to target BTICs isolated from medulloblastoma, atypical teratoid/rhabdoid tumors (AT/RT) and glioblastoma. Different types of cyto-chemokines are involved in the crosstalk between hAT-MSCs and BTICs (medulloblastoma and AT/RT: CXCR4/SDF-1, CCR5/RANTES, IL6R/IL-6 and IL8R/IL8; glioblastoma: CXCR4/SDF-1, IL6R/IL-6, IL8R/IL-8 and IGF1R/IGF-1). Our findings demonstrated the migratory ability of hAT-MSCs for BTICs, implying the potential use of MSCs as a delivery vehicle for gene therapy. This study also confirmed the expression of hAT-MSCs cytokine receptors and the BTIC ligands that play roles in their crosstalk.
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, College of Medicine, Seoul, Korea; Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Seung Ah
authors.initials: SA
authors.lastname: Choi
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, College of Medicine, Seoul, Korea; Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ji Yeoun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kwon
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, College of Medicine, Seoul, Korea; Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Kyu-Chang
authors.initials: KC
authors.lastname: Wang
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, College of Medicine, Seoul, Korea; Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Phi
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, College of Medicine, Seoul, Korea; Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Jung Won
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Cell Growth Regulation Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Xiong
authors.initials: X
authors.lastname: Jin
authors.affiliation: Cell Growth Regulation Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Ja Yun
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Cell Growth Regulation Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Hyunggee
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, College of Medicine, Seoul, Korea; Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002469:Cell Separation / Q000379:methods; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D018121:Receptors, Cytokine