title: Pathological classification of human iPSC-derived neural stem/progenitor cells towards safety assessment of transplantation therapy for CNS diseases.
abstract: The risk of tumorigenicity is a hurdle for regenerative medicine using induced pluripotent stem cells (iPSCs). Although teratoma formation is readily distinguishable, the malignant transformation of iPSC derivatives has not been clearly defined due to insufficient analysis of histology and phenotype. In the present study, we evaluated the histology of neural stem/progenitor cells (NSPCs) generated from integration-free human peripheral blood mononuclear cell (PBMC)-derived iPSCs (iPSC-NSPCs) following transplantation into central nervous system (CNS) of immunodeficient mice. We found that transplanted iPSC-NSPCs produced differentiation patterns resembling those in embryonic CNS development, and that the microenvironment of the final site of migration affected their maturational stage. Genomic instability of iPSCs correlated with increased proliferation of transplants, although no carcinogenesis was evident. The histological classifications presented here may provide cues for addressing potential safety issues confronting regenerative medicine involving iPSCs.
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.|Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sugai
authors.affiliation: Department of Pathology, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, 183-8561, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuzawa
authors.affiliation: Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Chuo-ku, Osaka, 540-0006, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shofuda
authors.affiliation: Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Chuo-ku, Osaka, 540-0006, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Fukusumi
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.|Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Soya
authors.initials: S
authors.lastname: Kawabata
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.|Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nishiyama
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, 210-0821, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, 210-0821, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.|Regenerative & Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Kobe, Hyogo, 650-0047, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Isoda
authors.affiliation: Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Chuo-ku, Osaka, 540-0006, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kanematsu
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hashimoto-Tamaoki
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kohyama
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Iwanami
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, 210-0821, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Chuo-ku, Osaka, 540-0006, Japan.|Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Chuo-ku, Osaka, 540-0006, Japan.
authors.forename: Yonehiro
authors.initials: Y
authors.lastname: Kanemura
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan. hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002493:Central Nervous System Diseases / Q000473:pathology / Q000628:therapy*; D042822:Genomic Instability; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology* / Q000637:transplantation; D059785:Karyotype; D016513:Mice, SCID; D008954:Models, Biological; D058953:Neural Stem Cells / Q000473:pathology* / Q000637:transplantation; D012042:Registries; D033581:Stem Cell Transplantation / Q000009:adverse effects*
keywords: Carcinogenesis; Cell transplantation; Human induced pluripotent stem cells; Pathology; Regenerative medicine