Clinically applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem gliomas

• Published in: Cancer gene therapy Vol. 22; no. 6; pp. 302 - 311
• Main Authors: Choi, S A, Lee, Y E, Kwak, P A, Lee, J Y, Kim, S S, Lee, S J, Phi, J H, Wang, K-C, Song, J, Song, S H, Joo, K M, Kim, S-K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2015; Nature Publishing Group
• Subjects: 13/100; 14/63; 42/100; 42/44; 45/77; 45/90; 631/67/1922; 64/60; 82/29; 82/80; Adipose tissue; Adipose Tissue - cytology; Animals; Apoptosis; Autografts; Biomedical and Life Sciences; Biomedicine; Body fat; Brain cancer; Brain stem; Brain Stem Neoplasms - therapy; Cancer; Care and treatment; Cell Line, Tumor; Development and progression; Esterase; Female; Gene Expression; Gene Therapy; Genes; Genetic aspects; Genetic engineering; Genetic research; Genetic Therapy - methods; Genetic transformation; Genomics; Glioma; Glioma - therapy; Gliomas; Good Manufacturing Practice; Health aspects; Humans; Malignancy; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stromal Cells - metabolism; Methods; Mice; Oncology, Experimental; original-article; Patient outcomes; Stem cell transplantation; Stem cells; Therapeutic applications; TNF-Related Apoptosis-Inducing Ligand - genetics; TRAIL protein; Transgenes; Transplantation; Tropism; Xenograft Model Antitumor Assays; South Korea
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2015.25

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.