Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors
Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors
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DOI：
10.1038/s41422-019-0251-7
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发表时间：
2020-01-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Jinyong
中科院分区：
文献类型：
--
作者：
Guo, Rongqun;Hu, Fangxiao;Wang, Jinyong
从多能干细胞（PSC）获得具有免疫活性和治疗性的T淋巴细胞生成是T细胞再生医学的中心目标。迄今为止，优先重建T淋巴细胞在体内从PSC仍然是一个实际的挑战。在这里，我们记录了Runx 1和Hoxa 9的协同和瞬时表达限制在PSC分化方案（iR 9-PSC）中的内皮向造血转变和造血成熟阶段的时间窗中，在体外诱导优先产生能够归巢到胸腺并在原发性和继发性免疫缺陷受者中发育成成熟T细胞的可移植造血祖细胞。单细胞转录组和功能分析说明了从PSC诱导T谱系的细胞轨迹，揭示了早在生血内皮细胞阶段确定的T谱系特化，并鉴定了真正的前胸腺祖细胞。诱导的T细胞在中枢和外周淋巴器官中分布正常，并显示出丰富的TCR α β库。再生T淋巴细胞生成恢复免疫缺陷小鼠的免疫监视。此外，基因编辑的iR 9-PSC在体内产生了肿瘤特异性T细胞，有效地根除了肿瘤细胞。这项研究提供了从无限和可编辑的PSC来源通用生成功能性和治疗性T细胞的见解。
Achievement of immunocompetent and therapeutic T lymphopoiesis from pluripotent stem cells (PSCs) is a central aim in T cell regenerative medicine. To date, preferentially reconstituting T lymphopoiesis in vivo from PSCs remains a practical challenge. Here we documented that synergistic and transient expression of Runx1 and Hoxa9 restricted in the time window of endothelial-to-hematopoietic transition and hematopoietic maturation stages in a PSC differentiation scheme (iR9-PSC) in vitro induced preferential generation of engraftable hematopoietic progenitors capable of homing to thymus and developing into mature T cells in primary and secondary immunodeficient recipients. Single-cell transcriptome and functional analyses illustrated the cellular trajectory of T lineage induction from PSCs, unveiling the T-lineage specification determined at as early as hemogenic endothelial cell stage and identifying the bona fide pre-thymic progenitors. The induced T cells distributed normally in central and peripheral lymphoid organs and exhibited abundant TCR alpha beta repertoire. The regenerative T lymphopoiesis restored immune surveillance in immunodeficient mice. Furthermore, gene-edited iR9-PSCs produced tumor-specific T cells in vivo that effectively eradicated tumor cells. This study provides insight into universal generation of functional and therapeutic T cells from the unlimited and editable PSC source.