Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs.
Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs.
复制标题
早期造血的单细胞转录组指导人类 PSC 生成动脉内皮增强功能性 T 细胞
DOI：
10.1126/sciadv.abi9787
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发表时间：
2021-09-03
期刊：
影响因子：
13.6
通讯作者：
Cheng T
中科院分区：
文献类型：
--
作者：
Shen J;Xu Y;Zhang S;Lyu S;Huo Y;Zhu Y;Tang K;Mou J;Li X;Hoyle DL;Wang M;Wang J;Li X;Wang ZZ;Cheng T
低氧通过动脉启动增强具有功能性T细胞潜能的人多能干细胞的造血功能。人类多能干细胞(HPSCs)的造血分化需要动态的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分析，以绘制hPSCs在造血分化过程中的命运选择和基因表达模式，并显示在体外定向分化过程中氧化代谢受到失调。在体外内皮细胞向造血细胞转化阶段应用低氧条件，有效地促进了动脉规范程序的发展，这些程序控制着具有功能T细胞潜能的造血祖细胞的生成。在基因工程表达抗CD19嵌合抗原受体后，动脉内皮细胞诱导的HPC产生的T细胞在体外和体内都抑制了肿瘤的生长。总而言之，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，并代表了在指导临床应用的功能T细胞体外生成方面的进步。
Hypoxia enhances hematopoiesis with functional T cell potential from human pluripotent stem cells via arterial priming. 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.
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