title: Enhanced tumor growth inhibition by mesenchymal stem cells derived from iPSCs with targeted integration of interleukin24 into rDNA loci.
abstract: Induced pluripotent stem cells (iPSCs) are a promising source of mesenchymal stem cells (MSCs) for clinical applications. In this study, we transformed human iPSCs using a non-viral vector carrying the IL24 transgene pHrn-IL24. PCR and southern blotting confirmed IL24 integration into the rDNA loci in four of 68 iPSC clones. We then differentiated a high expressing IL24-iPSC clone into MSCs (IL24-iMSCs) that showed higher expression of IL24 in culture supernatants and in cell lysates than control iMSCs. IL24-iMSCs efficiently differentiated into osteoblasts, chondrocytes and adipocytes. Functionally, IL24-iMSCs induced in vitro apoptosis in B16-F10 melanoma cells more efficiently than control iMSCs when co-cultured in Transwell assays. In vivo tumor xenograft studies in mice demonstrated that IL24-iMSCs inhibited melanoma growth more than control iMSCs did. Immunofluorescence and histochemical analysis showed larger necrotic areas and cell nuclear aggregation in tumors with IL24-iMSCs than control iMSCs, indicating that IL24-iMSCs inhibited tumor growth by inducing apoptosis. These findings demonstrate efficient transformation of iPSCs through gene targeting with non-viral vectors into a rDNA locus. The ability of these genetically modified MSCs to inhibit in vivo melanoma growth is suggestive of the clinical potential of autologous cell therapy in cancer.
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Mai
authors.initials: M
authors.lastname: Feng
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Miaojin
authors.initials: M
authors.lastname: Zhou
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Yanchi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Lingqian
authors.initials: L
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Xionghao
authors.initials: X
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Liang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007621:Karyotyping; D008297:Male; D008546:Melanoma, Experimental / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
chemical_list: D004275:DNA, Ribosomal; D007378:Interleukins; D000099180:Interleukin-24
keywords: IL24; MSCs derived from iPSCs; anti-tumor; gene targeting; rDNA locus