title: GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells.
abstract: WNT/β-CATENIN signaling promotes the hematopoietic/endothelial differentiation of human embryonic stem cells and human induced pluripotent stem cells (hiPSCs). The transient addition of a GSK3β inhibitor (GSKi) has been found to facilitate in vitro endothelial cell differentiation from hESCs/hiPSCs. Because hematopoietic and endothelial cells are derived from common progenitors (hemogenic endothelial progenitors [HEPs]), we examined the effect of transient GSKi treatment on hematopoietic cell differentiation from hiPSCs. We found that transient GSKi treatment at the start of hiPSC differentiation induction altered the gene expression profile of the cells. Multiple CDX/HOX genes, which are expressed in the posterior mesoderm of developing embryos, were significantly upregulated by GSKi treatment. Further, inclusion of the GSKi in a serum- and stroma-free culture with chemically defined medium efficiently induced HEPs, and the HEPs gave rise to various lineages of hematopoietic and endothelial cells. Therefore, transient WNT/β-CATENIN signaling triggers activation of the CDX/HOX pathway, which in turn confers hemogenic posterior mesoderm identity to differentiating hiPSCs. These data enhance our understanding of human embryonic hematopoietic/endothelial cell development and provide a novel in vitro system for inducing the differentiation of hematopoietic cells from hiPSCs.
authors.affiliation: Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address: kitajima-kj@igakuken.or.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitajima
authors.affiliation: Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Marino
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Kanokoda
authors.affiliation: Lillehei Heart Institute, Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.affiliation: Lillehei Heart Institute, Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dandapat
authors.affiliation: Pediatric Hematology-Oncology, Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.affiliation: Clinical Application Department, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Megumu K
authors.initials: MK
authors.lastname: Saito
authors.affiliation: Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Toyoda
authors.affiliation: Department of Reproductive Biology and Pathology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.affiliation: Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hara
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005801:Genes, Homeobox; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3