Therapeutic efficacy and safety of TRAIL-producing human adipose tissue-derived mesenchymal stem cells against experimental brainstem glioma.
Mesenchymal stem cells (MSCs) have an extensive migratory capacity for gliomas, which is comparable to that of neural stem cells. Among the various types of MSCs, human adipose tissue-derived MSCs (hAT-MSC) emerge as one of the most attractive vehicles for gene therapy because of their high throughput, lack of ethical concerns, and availability and ease of isolation. We evaluated the therapeutic potential and safety of genetically engineered hAT-MSCs encoding the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against brainstem gliomas. Human AT-MSCs were isolated from human fat tissue, characterized, and transfected with TRAIL using nucleofector. The therapeutic potential of TRAIL-producing hAT-MSCs (hAT-MSC.TRAIL) was confirmed using in vitro and in vivo studies. The final fate of injected hAT-MSCs was traced in long-survival animals. The characterization of hAT-MSCs revealed the expression of MSC-specific cell-type markers and their differentiation potential into mesenchymal lineage. Short-term outcomes included a 56.3% reduction of tumor volume (P < .001) with increased apoptosis (3.03-fold, P < .05) in animals treated with hAT-MSC.TRAIL compared with the control groups. Long-term outcomes included a significant survival benefit in the hAT-MSC.TRAIL-treated group (26 days of median survival in the control group vs 84 days in the hAT-MSC.TRAIL-treated group, P < .0001), without any evidence of mesenchymal differentiation in vivo. Our study demonstrated the therapeutic efficacy and safety of nonvirally engineered hAT-MSCs against brainstem gliomas and showed the possibility of stem-cell-based targeted gene therapy for clinical application.
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehagno, Jongno-gu, Seoul 110-744, South Korea.
Seung Ah
SA
Choi
Sung-Kyun
SK
Hwang
Kyu-Chang
KC
Wang
Byung-Kyu
BK
Cho
Ji Hoon
JH
Phi
Ji Yeoun
JY
Lee
Hee Won
HW
Jung
Do-Hun
DH
Lee
Seung-Ki
SK
Kim
D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D020295:Brain Stem Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand