Hematopoietic differentiation of human pluripotent stem cells (hPSCs) requires orchestration of dynamic cell and gene regulatory networks but often generates blood cells that lack natural function. Here, we performed extensive single-cell transcriptomic analyses to map fate choices and gene expression patterns during hematopoietic differentiation of hPSCs and showed that oxidative metabolism was dysregulated during in vitro directed differentiation. Applying hypoxic conditions at the stage of endothelial-to-hematopoietic transition in vitro effectively promoted the development of arterial specification programs that governed the generation of hematopoietic progenitor cells (HPCs) with functional T cell potential. Following engineered expression of the anti-CD19 chimeric antigen receptor, the T cells generated from arterial endothelium-primed HPCs inhibited tumor growth both in vitro and in vivo. Collectively, our study provides benchmark datasets as a resource to further understand the origins of human hematopoiesis and represents an advance in guiding in vitro generation of functional T cells for clinical applications.

中文翻译：

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早期造血的单细胞转录组指导人 PSCs 产生动脉内皮增强功能性 T 细胞

人类多能干细胞 (hPSC) 的造血分化需要动态细胞和基因调控网络的协调，但通常会产生缺乏自然功能的血细胞。在这里，我们进行了广泛的单细胞转录组学分析，以绘制 hPSC 造血分化过程中的命运选择和基因表达模式，并表明在体外定向分化过程中氧化代谢失调。在内皮细胞向造血细胞转变阶段应用缺氧条件可有效促进动脉规范程序的发展，该程序控制具有功能性 T 细胞潜能的造血祖细胞 (HPC) 的生成。在工程化表达抗 CD19 嵌合抗原受体后，由动脉内皮引发的 HPC 产生的 T 细胞在体外和体内均抑制肿瘤生长。总的来说，我们的研究提供了基准数据集作为进一步了解人类造血起源的资源，并代表了指导体外生成功能性 T 细胞用于临床应用的进步。