title: Clinically applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem gliomas.
abstract: Pediatric brainstem glioma is an incurable malignancy because of its inoperability. As a result of their extensive tropism toward cancer and the possibility of autologous transplantation, human adipose-derived mesenchymal stem cells (hAT-MSC) are attractive vehicles to deliver therapeutic genes to brainstem gliomas. In this study, in a good manufacturing practice (GMP) facility, we established clinically applicable hAT-MSCs expressing therapeutic genes and investigated their therapeutic efficacy against brainstem glioma in mice. For feasible clinical applications, (1) primary hAT-MSCs were cultured from human subcutaneous fat to make autologous transplantation possible, (2) hAT-MSCs were genetically engineered to express carboxyl esterase (CE) and (3) a secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) expression vector for synergistic effects was delivered by a gene transfer technology that did not result in genomic integration of the vector. (4) Human CE and sTRAIL sequences were utilized to avoid immunological side effects. The hAT-MSCs expressing CE±sTRAIL showed significant therapeutic effects against brainstem gliomas in vitro and in vivo. However, the simultaneous expression of CE and sTRAIL had no synergistic effects in vivo. The results indicate that non-viral transient single sTRAIL gene transfer to autologous hAT-MSCs is a clinically applicable stem cell-based gene therapy for brainstem gliomas in terms of therapeutic effects and safety.
authors.affiliation: 1] Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea.
authors.forename: S A
authors.initials: SA
authors.lastname: Choi
authors.affiliation: 1] Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Y E
authors.initials: YE
authors.lastname: Lee
authors.affiliation: 1] Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea.
authors.forename: P A
authors.initials: PA
authors.lastname: Kwak
authors.affiliation: 1] Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: S S
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University, School of Medicine, Suwon, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: 1] Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Phi
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: K-C
authors.initials: KC
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Song
authors.affiliation: 1] Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea [2] Department of Anatomy and Cell Biology, Sungkyunkwan University, School of Medicine, Suwon, Republic of Korea [3] Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: K M
authors.initials: KM
authors.lastname: Joo
authors.affiliation: 1] Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea.
authors.forename: S-K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D020295:Brain Stem Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000628:therapy*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand