Abstract
Changes in cell fate and identity are essential for endothelial-to-haematopoietic transition (EHT), an embryonic process that generates the first adult populations of haematopoietic stem cells (HSCs) from hemogenic endothelial cells. Dissecting EHT regulation is a critical step towards the production of in vitro derived HSCs. Yet, we do not know how distinct endothelial and haematopoietic fates are parsed during the transition. Here we show that genes required for arterial identity function later to repress haematopoietic fate. Tissue-specific, temporally controlled, genetic loss of arterial genes (Sox17 and Notch1) during EHT results in increased production of haematopoietic cells due to loss of Sox17-mediated repression of haematopoietic transcription factors (Runx1 and Gata2). However, the increase in EHT can be abrogated by increased Notch signalling. These findings demonstrate that the endothelial haematopoietic fate switch is actively repressed in a population of endothelial cells, and that derepression of these programs augments haematopoietic output.
Highlights
Changes in cell fate and identity are essential for endothelial-to-haematopoietic transition (EHT), an embryonic process that generates the first adult populations of haematopoietic stem cells (HSCs) from hemogenic endothelial cells
The endothelium of this region can be identified by immunofluorescence of the pan-endothelial cells (ECs) surface marker PECAM-1 (CD31), and haematopoietic stem and progenitor cells (HSPCs) clusters are apparent through their rounded morphology and shared endothelial marker expression (Fig. 1a–d)
It may be that hemogenic endothelial specification requires the same pathways mobilized in the acquisition of arterial identity, but not arterial identity per se
Summary
Changes in cell fate and identity are essential for endothelial-to-haematopoietic transition (EHT), an embryonic process that generates the first adult populations of haematopoietic stem cells (HSCs) from hemogenic endothelial cells. The increase in EHT can be abrogated by increased Notch signalling These findings demonstrate that the endothelial haematopoietic fate switch is actively repressed in a population of endothelial cells, and that derepression of these programs augments haematopoietic output. Sox[17] positively regulates Notch[1] for both arterial fate acquisition and hemogenic endothelial specification[22,26] How these arterial fate specifiers function in endothelial to haematopoietic conversion, separate from their role in artery–vein specification, is unclear. We present data that demonstrates after artery–vein specification, Sox[17] actively prevents the transition to haematopoietic fate by repression of key haematopoietic transcription factors, thereby maintaining endothelial identity. The loss of Sox[17] promotes haematopoietic conversion, and its dynamic expression imparts a previously unappreciated, but critical step, in endothelial to haematopoietic cell fate transition
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