title: Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas.
abstract: Human mesenchymal stem cells (hMSCs) have emerged as attractive cellular vehicles for gene therapy against brain malignancy because of their targeted tropism for cancer and the intrinsic attribute of autologous transplantation. We evaluated the characteristics and therapeutic potential of human adipose tissue-derived MSCs (hAT-MSCs) and prodrug gene therapy against diffuse pontine gliomas. The hAT-MSCs were isolated from human adipose tissue and characterised for morphology, surface markers and potential to differentiate into mesenchymal and neuronal lineages. We genetically modified hAT-MSCs to express rabbit carboxylesterase (rCE) enzyme, which can efficiently convert the prodrug CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin), into the active drug SN-38 (7-ethyl-10-hydroxycamptothecin). The migratory capacity of hAT-MSCs expressing rCE (hAT-MSC.rCE), their ability to convert CPT-11 to SN-38 and cytotoxic effect on F98 cells were evaluated in vitro. The therapeutic potential of hAT-MSC.rCE was confirmed using a rat brainstem glioma model. The hAT-MSCs showed fibroblast-like morphology and expressed hMSC-specific markers including CD73, CD90 and CD105. The hAT-MSCs could differentiate into a mesenchymal lineage and transdifferentiate into a neuronal lineage under optimum culture conditions. The hAT-MSC.rCE converted CPT-11 to SN-38 and preserved the tumour tropism of hAT-MSCs. Brainstem glioma-bearing rats treated with hAT-MSC.rCE and CPT-11 survived 5d more than rats treated with CPT-11 only (p=0.0018). Our study demonstrates that hAT-MSCs can be easily prepared and genetically modified as cellular vehicles for prodrug gene therapy and that they have therapeutic potential against brainstem gliomas.
authors.affiliation: Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung Ah
authors.initials: SA
authors.lastname: Choi
authors.forename: Ji Yeoun
authors.initials: JY
authors.lastname: Lee
authors.forename: Kyu-Chang
authors.initials: KC
authors.lastname: Wang
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Phi
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Song
authors.forename: Junghan
authors.initials: J
authors.lastname: Song
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D020295:Brain Stem Neoplasms / Q000235:genetics / Q000628:therapy*; D043182:Carboxylesterase / Q000008:administration & dosage / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D004337:Drug Carriers / Q000378:metabolism; D056947:Enzyme Replacement Therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004337:Drug Carriers; D011355:Prodrugs; D043182:Carboxylesterase