Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
Nat Commun. 2024 Sep 4;15(1):7698. doi: 10.1038/s41467-024-51974-7.
Arterial endothelial cells (AECs) are the founder cells for intraembryonic haematopoiesis. Here, we report a method for the efficient generation of human haemogenic DLL4+ AECs from pluripotent stem cells (PSC). Time-series single-cell RNA-sequencing reveals the dynamic evolution of haematopoiesis and lymphopoiesis, generating cell types with counterparts present in early human embryos, including stages marked by the pre-haematopoietic stem cell genes MECOM/EVI1, MLLT3 and SPINK2. DLL4+ AECs robustly support lymphoid differentiation, without the requirement for exogenous NOTCH ligands. Using this system, we find IL7 acts as a morphogenic factor determining the fate choice between the T and innate lymphoid lineages and also plays a role in regulating the relative expression level of RAG1. Moreover, we document a developmental pathway by which human RAG1+ lymphoid precursors give rise to the natural killer cell lineage. Our study describes an efficient method for producing lymphoid progenitors, providing insights into their endothelial and haematopoietic ontogeny, and establishing a platform to investigate the development of the human blood system.
动脉内皮细胞（AECs）是胚胎内造血的创始细胞。在这里，我们报告了一种从多能干细胞（PSC）高效生成人类造血 DLL4+AEC 的方法。时间序列单细胞 RNA 测序揭示了造血和淋巴发生的动态演变，产生了与早期人类胚胎中存在的细胞类型相对应的细胞类型，包括由造血干细胞基因 MECOM/EVI1、MLLT3 和 SPINK2 标记的阶段。DLL4+AEC 可强有力地支持淋巴分化，而无需外源性 NOTCH 配体。使用该系统，我们发现 IL7 作为一种形态发生因子，决定了 T 和固有淋巴谱系之间命运选择，并在调节 RAG1 的相对表达水平方面发挥作用。此外，我们记录了一条人类 RAG1+淋巴前体细胞产生自然杀伤细胞谱系的发育途径。我们的研究描述了一种高效产生淋巴祖细胞的方法，为它们的内皮和造血发生提供了深入了解，并建立了一个平台来研究人类血液系统的发育。
