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Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors.
Cell Research ( IF 28.1 ) Pub Date : 2019-11-15 , DOI: 10.1038/s41422-019-0251-7
Rongqun Guo 1, 2, 3, 4, 5 , Fangxiao Hu 1, 2, 4, 5 , Qitong Weng 1, 2, 3, 4, 5 , Cui Lv 1, 2, 4, 5 , Hongling Wu 1, 2, 4, 5 , Lijuan Liu 1, 2, 4, 5, 6 , Zongcheng Li 7 , Yang Zeng 7 , Zhijie Bai 7 , Mengyun Zhang 1, 2, 4, 5, 6 , Yuting Liu 1, 2, 4, 5 , Xiaofei Liu 1, 2, 4, 5, 6 , Chengxiang Xia 1, 2, 3, 4, 5 , Tongjie Wang 1, 2, 4, 5 , Peiqing Zhou 1, 2, 3, 4, 5 , Kaitao Wang 1, 2, 4, 5, 6 , Yong Dong 1, 2, 4, 5 , Yuxuan Luo 8 , Xiangzhong Zhang 8 , Yuxian Guan 1, 2, 4, 5 , Yang Geng 1, 2, 4, 5, 6 , Juan Du 1, 2, 3, 4, 5 , Yangqiu Li 9 , Yu Lan 9 , Jiekai Chen 1, 2, 3, 4, 5, 6 , Bing Liu 7 , Jinyong Wang 1, 2, 3, 4, 5, 6
Affiliation  

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 TCRαβ 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.

中文翻译:

通过确定的转录因子指导多能干细胞的 T 淋巴细胞生成。

从多能干细胞 (PSC) 中实现免疫活性和治疗性 T 淋巴细胞生成是 T 细胞再生医学的核心目标。迄今为止,优先从 PSC 体内重建 T 淋巴细胞生成仍然是一个实际挑战。在这里,我们记录了 Runx1 和 Hoxa9 的协同和瞬时表达限制在 PSC 分化方案(iR9-PSC) 体外 诱导优先产生能够归巢的可移植造血祖细胞的内皮到造血转换和造血成熟阶段的时间窗口到胸腺并在原发性和继发性免疫缺陷受体中发育成成熟的 T 细胞。单细胞转录组和功能分析说明了 PSC 诱导 T 谱系的细胞轨迹,揭示了早在造血内皮细胞阶段就确定的 T 谱系规范,并确定了真正的胸腺前祖细胞。诱导的 T 细胞在中枢和外周淋巴器官中正常分布,并表现出丰富的 TCRαβ 库。再生 T 淋巴细胞生成恢复了免疫缺陷小鼠的免疫监视。此外,基因编辑的 iR9-PSC 在体内产生肿瘤特异性 T 细胞,可有效根除肿瘤细胞。这项研究提供了从无限和可编辑的 PSC 来源中普遍生成功能性和治疗性 T 细胞的见解。再生 T 淋巴细胞生成恢复了免疫缺陷小鼠的免疫监视。此外,基因编辑的 iR9-PSC 在体内产生肿瘤特异性 T 细胞,可有效根除肿瘤细胞。这项研究提供了从无限和可编辑的 PSC 来源中普遍生成功能性和治疗性 T 细胞的见解。再生 T 淋巴细胞生成恢复了免疫缺陷小鼠的免疫监视。此外,基因编辑的 iR9-PSC 在体内产生肿瘤特异性 T 细胞,可有效根除肿瘤细胞。这项研究提供了从无限和可编辑的 PSC 来源中普遍生成功能性和治疗性 T 细胞的见解。
更新日期:2019-11-15
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