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Analysis of endothelial-to-haematopoietic transition at the single cell level identifies cell cycle regulation as a driver of differentiation.

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Canu, Giovanni 
Athanasiadis, Emmanouil 
Grandy, Rodrigo A 
Garcia-Bernardo, Jose 
Strzelecka, Paulina M 


BACKGROUND: Haematopoietic stem cells (HSCs) first arise during development in the aorta-gonad-mesonephros (AGM) region of the embryo from a population of haemogenic endothelial cells which undergo endothelial-to-haematopoietic transition (EHT). Despite the progress achieved in recent years, the molecular mechanisms driving EHT are still poorly understood, especially in human where the AGM region is not easily accessible. RESULTS: In this study, we take advantage of a human pluripotent stem cell (hPSC) differentiation system and single-cell transcriptomics to recapitulate EHT in vitro and uncover mechanisms by which the haemogenic endothelium generates early haematopoietic cells. We show that most of the endothelial cells reside in a quiescent state and progress to the haematopoietic fate within a defined time window, within which they need to re-enter into the cell cycle. If cell cycle is blocked, haemogenic endothelial cells lose their EHT potential and adopt a non-haemogenic identity. Furthermore, we demonstrate that CDK4/6 and CDK1 play a key role not only in the transition but also in allowing haematopoietic progenitors to establish their full differentiation potential. CONCLUSION: We propose a direct link between the molecular machineries that control cell cycle progression and EHT.



Cell Cycle, Cell Differentiation, Cyclin-Dependent Kinases, Endothelial Cells, Hematopoiesis, Hematopoietic Stem Cells, Humans, Pluripotent Stem Cells, Single-Cell Analysis

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Genome Biol

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Springer Science and Business Media LLC


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Cancer Research Uk (None)
European Research Council (677501)
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_12009)
Medical Research Council (G0701448)
National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/N001540/1)
European Research Council (741707)
Engineering and Physical Sciences Research Council (TS/H001220/1)
Medical Research Council (MC_PC_17230)
European Commission Horizon 2020 (H2020) Societal Challenges (668294-2 INTENS)
Medical Research Council (MR/M008975/1)
This research was supported by a British Heart Foundation PhD Studentship as part of the BHF Oxbridge Centre of Regenerative Medicine (G.C.); Cancer Research UK grant number C45041/A14953 (A.C. and E.A.); European Research Council project 677501 – ZF_Blood (A.C.); the INTENS EU fp8 consortium (D.O); the ERC advanced grant New-Chol (R.G. and L.V.); the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre (R.G., D.O. and L.V.); and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute. The work was also supported by the Cambridge NIHR BRC Cell Phenotyping Hub.
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