GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells

Kenji Kitajima, Marino Nakajima, Mai Kanokoda, Michael Kyba, Abhijit Dandapat, Jakub Tolar, Megumu K. Saito, Masashi Toyoda, Akihiro Umezawa, Takahiko Hara

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)68-74.e10
JournalExperimental Hematology
Volume44
Issue number1
DOIs
StatePublished - Jan 1 2016

Bibliographical note

Funding Information:
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan ( 24591415 to KK and 23390256 to KK and TH), a Grant-in-Aid for Research on Hepatitis from the Ministry of Health, Labour and Welfare , and the SENSHIN Medical Research Foundation.

Publisher Copyright:
© 2016 ISEH - International Society for Experimental Hematology.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

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