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Stem Cell Reports. 2017 Sep 12;9(3):779-795. doi: 10.1016/j.stemcr.2017.07.011. Epub 2017 Aug 10.

Targeted Disruption of TCF12 Reveals HEB as Essential in Human Mesodermal Specification and Hematopoiesis.

Author information

1
Department of Immunology, University of Toronto, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University, Beijing, 100191, China.
2
Department of Immunology, University of Toronto, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
3
Department of Immunology, University of Toronto, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada. Electronic address: jczp@sri.utoronto.ca.
4
Department of Immunology, University of Toronto, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada. Electronic address: manderso@sri.utoronto.ca.

Abstract

Hematopoietic stem cells arise from mesoderm-derived hemogenic endothelium (HE) during embryogenesis in a process termed endothelial-hematopoietic transition (EHT). To better understand the gene networks that control this process, we investigated the role of the transcription factor HEB (TCF12) by disrupting the TCF12 gene locus in human embryonic stem cells (hESCs) and inducing them to differentiate toward hematopoietic outcomes. HEB-deficient hESCs retained key features of pluripotency, including expression of SOX2 and SSEA-4 and teratoma formation, while NANOG expression was reduced. Differentiation of HEB-/- hESCs toward hematopoietic fates revealed a severe defect in mesodermal development accompanied by decreased expression of regulators of mesoendodermal fate choices. We also identified independent defects in HE formation at the molecular and cellular levels, as well as a failure of T cell development. All defects were largely rescued by re-expression of HEB. Taken together, our results identify HEB as a critical regulator of human mesodermal and hematopoietic specification.

KEYWORDS:

HEB; Notch1; Runx1; T cell development; genome editing; hematopoiesis; hemogenic endothelium; human embryonic stem cell; mesoderm; transcriptional regulation

PMID:
28803914
PMCID:
PMC5599183
DOI:
10.1016/j.stemcr.2017.07.011
[Indexed for MEDLINE]
Free PMC Article

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