RT Journal Article
SR Electronic
T1 Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.03.023762
DO 10.1101/2020.04.03.023762
A1 Giovanni Canu
A1 Emmanouil Athanasiadis
A1 Rodrigo A. Grandy
A1 Jose Garcia-Bernardo
A1 Paulina M. Strzelecka
A1 Ludovic Vallier
A1 Daniel Ortmann
A1 Ana Cvejic
YR 2020
UL http://biorxiv.org/content/early/2020/04/04/2020.04.03.023762.abstract
AB Haematopoietic stem cells (HSC) 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. In this study, we took 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 demonstrated 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. Therefore, we propose a direct link between the molecular machineries that control cell cycle progression and EHT.