title: Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis.
abstract: HAX1 was identified as the gene responsible for the autosomal recessive type of severe congenital neutropenia. However, the connection between mutations in the HAX1 gene and defective granulopoiesis in this disease has remained unclear, mainly due to the lack of a useful experimental model for this disease. In this study, we generated induced pluripotent stem cell lines from a patient presenting for severe congenital neutropenia with HAX1 gene deficiency, and analyzed their in vitro neutrophil differentiation potential by using a novel serum- and feeder-free directed differentiation culture system. Cytostaining and flow cytometric analyses of myeloid cells differentiated from patient-derived induced pluripotent stem cells showed arrest at the myeloid progenitor stage and apoptotic predisposition, both of which replicated abnormal granulopoiesis. Moreover, lentiviral transduction of the HAX1 cDNA into patient-derived induced pluripotent stem cells reversed disease-related abnormal granulopoiesis. This in vitro neutrophil differentiation system, which uses patient-derived induced pluripotent stem cells for disease investigation, may serve as a novel experimental model and a platform for high-throughput screening of drugs for various congenital neutrophil disorders in the future.
authors: heike@kuhp.kyoto-u.ac.jp.
authors: Tatsuya
authors: T
authors: Morishima
authors: Ken-ichiro
authors: K
authors: Watanabe
authors: Akira
authors: A
authors: Niwa
authors: Hideyo
authors: H
authors: Hirai
authors: Satoshi
authors: S
authors: Saida
authors: Takayuki
authors: T
authors: Tanaka
authors: Itaru
authors: I
authors: Kato
authors: Katsutsugu
authors: K
authors: Umeda
authors: Hidefumi
authors: H
authors: Hiramatsu
authors: Megumu K
authors: MK
authors: Saito
authors: Kousaku
authors: K
authors: Matsubara
authors: Souichi
authors: S
authors: Adachi
authors: Masao
authors: M
authors: Kobayashi
authors: Tatsutoshi
authors: T
authors: Nakahata
authors: Toshio
authors: T
authors: Heike
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002460:Cell Line; D002648:Child; D000080984:Congenital Bone Marrow Failure Syndromes; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D038042:Myelopoiesis / Q000235:genetics*; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000628:therapy; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human
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