title: A novel cell-sheet technology that achieves durable factor VIII delivery in a mouse model of hemophilia A.
abstract: Gene- or cell-based therapies aimed at creating delivery systems for coagulation factor VIII (FVIII) protein have emerged as promising options for hemophilia A treatment. However, several issues remain to be addressed regarding the efficacies and adverse events of these new classes of therapies. To improve an existing cell-based therapy involving the subcutaneous transplantation of FVIII-transduced blood outgrowth endothelial cells (BOECs), we employed a novel cell-sheet technology that allows individual dispersed cells to form a thin and contiguous monolayer without traditional bioabsorbable scaffold matrices. Compared to the traditional methodology, our cell-sheet approach resulted in longer-term and 3-5-fold higher expression of FVIII (up to 11% of normal) in recipient hemophilia A mice that lacked a FVIII humoral immune response due to transient immunosuppression with cyclophosphamide. Histological studies revealed that the transplanted BOEC sheets were structured as flat clusters, supporting the long-term expression of therapeutic FVIII in plasma from an ectopic subcutaneous space. Our novel tissue-engineering approach using genetically modified BOEC sheets could aid in development of cell-based therapy that will allow safe and effective in vivo delivery of functional FVIII protein in patients with hemophilia A.
authors.affiliation: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Regulatory Medicine for Thrombosis, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
authors.affiliation: Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.affiliation: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
authors.affiliation: Department of Regulatory Medicine for Thrombosis, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Matsui
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D005169:Factor VIII / Q000008:administration & dosage / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006467:Hemophilia A / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D005169:Factor VIII