Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
Department of Surgery, University of Cambridge, Cambridge, UK.
Genome Biol. 2020 Jul 1;21(1):157. doi: 10.1186/s13059-020-02058-4.
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.
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.
We propose a direct link between the molecular machineries that control cell cycle progression and EHT.
造血干细胞（HSCs）最初在胚胎的主动脉-性腺-中肾（AGM）区域的造血内皮细胞中从一群经历内皮-造血转化（EHT）的造血内皮细胞中出现。尽管近年来取得了进展，但驱动 EHT 的分子机制仍知之甚少，特别是在难以接近 AGM 区域的人类中。
在这项研究中，我们利用人类多能干细胞（hPSC）分化系统和单细胞转录组学在体外重现 EHT，并揭示了造血内皮细胞产生早期造血细胞的机制。我们表明，大多数内皮细胞处于静止状态，并在定义的时间窗口内进展为造血命运，在此期间，它们需要重新进入细胞周期。如果细胞周期被阻断，造血内皮细胞将失去 EHT 潜能并采用非造血特性。此外，我们证明 CDK4/6 和 CDK1 不仅在过渡中而且在允许造血祖细胞建立其完全分化潜能方面发挥关键作用。
我们提出了控制细胞周期进程和 EHT 的分子机制之间的直接联系。
