Analysis of endothelial-to-haematopoietic transition at the single cell level identifies cell cycle regulation as a driver of differentiation
Analysis of endothelial-to-haematopoietic transition at the single cell level identifies cell cycle regulation as a driver of differentiation
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DOI：
10.1186/s13059-020-02058-4
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发表时间：
2020-07-01
期刊：
影响因子：
12.3
通讯作者：
Cvejic, Ana
中科院分区：
文献类型：
--
作者：
Canu, Giovanni;Athanasiadis, Emmanouil;Cvejic, Ana
背景：造血干细胞(HSCs)最初起源于胚胎的主动脉-性腺-中肾(AGM)区，起源于一群经历内皮细胞向造血细胞转化(EHT)的造血内皮细胞。尽管近年来取得了进展，但对EHT的分子机制仍知之甚少，特别是在AGM区域不易到达的人类中。结果在本研究中，我们利用人多能干细胞(HPSC)分化系统和单细胞转录本，在体外概述了EHT，揭示了血源性内皮细胞产生早期造血细胞的机制。我们发现，大多数内皮细胞处于静止状态，并在特定的时间窗内走向造血命运，在此期间它们需要重新进入细胞周期。如果细胞周期受阻，造血性内皮细胞就会失去其EHT潜能，并采用非造血性身份。此外，我们证明CDK4/6和CDK1不仅在转化过程中发挥关键作用，而且在允许造血祖细胞充分分化的过程中也发挥着关键作用。结论我们提出了控制细胞周期进程的分子机制与EHT之间的直接联系。
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.