title: Production of functional coagulation factor VIII from iPSCs using a lentiviral vector.
abstract: The use of induced pluripotent stem cells (iPSCs) as an autologous cell source has shed new light on cell replacement therapy with respect to the treatment of numerous hereditary disorders. We focused on the use of iPSCs for cell-based therapy of haemophilia. We generated iPSCs from mesenchymal stem cells that had been isolated from C57BL/6 mice. The mouse iPSCs were generated through the induction of four transcription factor genes Oct3/4, Klf-4, Sox-2 and c-Myc. The derived iPSCs released functional coagulation factor VIII (FVIII) following transduction with a simian immunodeficiency virus vector. The subcutaneous transplantation of iPSCs expressing FVIII into nude mice resulted in teratoma formation, and significantly increased plasma levels of FVIII. The plasma concentration of FVIII was at levels appropriate for human therapy at 2-4 weeks post transplantation. Our data suggest that iPSCs could be an attractive and prospective autologous cell source for the production of coagulation factor, and that engineered iPSCs expressing coagulation factor might provide a cell-based therapeutic strategy appropriate for haemophilia.
authors.affiliation: Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kashiwakura
authors.forename: T
authors.initials: T
authors.lastname: Ohmori
authors.forename: J
authors.initials: J
authors.lastname: Mimuro
authors.forename: S
authors.initials: S
authors.lastname: Madoiwa
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Hasegawa
authors.forename: K
authors.initials: K
authors.lastname: Ozawa
authors.forename: Y
authors.initials: Y
authors.lastname: Sakata
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005169:Factor VIII / Q000096:biosynthesis* / Q000235:genetics*; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: D005169:Factor VIII
keywords: blood coagulation; cell therapy; gene therapy; haemophilia; induced pluripotent stem cells; lentiviral vector