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Stem Cell Reports. 2018 Apr 10;10(4):1369-1383. doi: 10.1016/j.stemcr.2018.03.011.

HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition.

Author information

1
CRUK Stem Cell Biology Group, CRUK Manchester Institute, 555 Wilmslow Road, Manchester M20 4GJ, UK.
2
Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK.
3
Division of Developmental Biology & Medicine, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK. Electronic address: valerie.kouskoff@manchester.ac.uk.
4
CRUK Stem Cell Biology Group, CRUK Manchester Institute, 555 Wilmslow Road, Manchester M20 4GJ, UK. Electronic address: georges.lacaud@manchester.ac.uk.

Abstract

The first hematopoietic stem and progenitor cells are generated during development from hemogenic endothelium (HE) through trans-differentiation. The molecular mechanisms underlying this endothelial-to-hematopoietic transition (EHT) remain poorly understood. Here, we explored the role of the epigenetic regulators HDAC1 and HDAC2 in the emergence of these first blood cells in vitro and in vivo. Loss of either of these epigenetic silencers through conditional genetic deletion reduced hematopoietic transition from HE, while combined deletion was incompatible with blood generation. We investigated the molecular basis of HDAC1 and HDAC2 requirement and identified TGF-β signaling as one of the pathways controlled by HDAC1 and HDAC2. Accordingly, we experimentally demonstrated that activation of this pathway in HE cells reinforces hematopoietic development. Altogether, our results establish that HDAC1 and HDAC2 modulate TGF-β signaling and suggest that stimulation of this pathway in HE cells would be beneficial for production of hematopoietic cells for regenerative therapies.

KEYWORDS:

AGM; HDAC1; HDAC2; TGF-β signaling; embryonic stem cells; endothelial-to-hematopoietic transition; epigenetic; hematopoietic stem cells; hemogenic endothelium; in vitro differentiation

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