title: Pluripotent cell models of fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors.
abstract: Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities, and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six patients with FA and FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF.
authors.affiliation: Departments of Clinical Application and.
authors.forename: Naoya M
authors.initials: NM
authors.lastname: Suzuki
authors.affiliation: Departments of Clinical Application and.
authors.forename: Akira
authors.initials: A
authors.lastname: Niwa
authors.affiliation: Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan;
authors.forename: Miharu
authors.initials: M
authors.lastname: Yabe
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan;
authors.forename: Asuka
authors.initials: A
authors.lastname: Hira
authors.affiliation: Reprogramming Science, Center for Induced Pluripotent Stem Cell Research and Application, and Mitsubishi Space Software Co., Ltd., Amagasaki, Japan;
authors.forename: Chihiro
authors.initials: C
authors.lastname: Okada
authors.affiliation: Reprogramming Science, Center for Induced Pluripotent Stem Cell Research and Application, and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Amano
authors.affiliation: Reprogramming Science, Center for Induced Pluripotent Stem Cell Research and Application, and.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan;
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.affiliation: Departments of Clinical Application and.
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.affiliation: Departments of Clinical Application and msaito@cira.kyoto-u.ac.jp.
authors.forename: Megumu K
authors.initials: MK
authors.lastname: Saito
mesh_terms: D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015316:Genetic Therapy; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D052217:Fanconi Anemia Complementation Group A Protein
keywords: Differentiation; Fanconi anemia; Hematopoietic progenitors; Induced pluripotent stem cells; Transcription factors