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Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors.

Rongqun GuoFangxiao HuQitong WengCui LvHongling WuLijuan LiuZongcheng LiYang ZengZhijie BaiMengyun ZhangYuting LiuXiaofei LiuChengxiang XiaTongjie WangPeiqing ZhouKaitao WangYong DongYuxuan LuoXiangzhong ZhangYuxian GuanYang GengJuan DuYangqiu LiYu LanJie-Kai ChenBing LiuJinyong Wang
Published in: Cell research (2019)
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.
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