Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3052, Australia.
Development. 2020 Oct 29;147(20):dev193037. doi: 10.1242/dev.193037.
The genetic regulatory network controlling early fate choices during human blood cell development are not well understood. We used human pluripotent stem cell reporter lines to track the development of endothelial and haematopoietic populations in an model of human yolk-sac development. We identified SOX17CD34CD43 endothelial cells at day 2 of blast colony development, as a haemangioblast-like branch point from which SOX17CD34CD43 blood cells and SOX17CD34CD43 endothelium subsequently arose. Most human blood cell development was dependent on RUNX1. Deletion of only permitted a single wave of yolk sac-like primitive erythropoiesis, but no yolk sac myelopoiesis or aorta-gonad-mesonephros (AGM)-like haematopoiesis. Blocking GFI1 and/or GFI1B activity with a small molecule inhibitor abrogated all blood cell development, even in cell lines with an intact gene. Together, our data define the hierarchical requirements for RUNX1, GFI1 and/or GFI1B during early human haematopoiesis arising from a yolk sac-like SOX17-negative haemogenic endothelial intermediate.
人类血液细胞发育过程中早期命运选择的遗传调控网络尚未被充分理解。我们使用人类多能干细胞报告系，在人类卵黄囊发育模型中追踪内皮细胞和造血细胞群体的发育。我们在胚集落发育的第 2 天鉴定出 SOX17CD34CD43 内皮细胞，作为一个类似血岛的分支点，此后 SOX17CD34CD43 血细胞和 SOX17CD34CD43 内皮细胞相继出现。大多数人类血液细胞发育依赖于 RUNX1。缺失 仅允许出现一波卵黄囊样原始红细胞生成，但没有卵黄囊粒细胞生成或主动脉-性腺-中肾（AGM）样造血。用小分子抑制剂阻断 GFI1 和/或 GFI1B 的活性会阻断所有的血细胞发育，即使在 基因完整的细胞系中也是如此。总之，我们的数据定义了 RUNX1、GFI1 和/或 GFI1B 在人类卵黄囊样 SOX17 阴性造血内皮中间产物中出现的早期造血过程中的层次需求。
