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Volume 30, No 1, Jan 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 1, January 2020: 21-33   |  Open Access

ORIGINAL ARTICLES

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

Rongqun Guo 1,2,3,5,6, Fangxiao Hu 1,2,5,6, Qitong Weng 1,2,3,5,6, Cui Lv 1,2,5,6, Hongling Wu 1,2,5,6, Lijuan Liu 1,2,4,5,6, Zongcheng Li 7,Yang Zeng7, Zhijie Bai 7, Mengyun Zhang 1,2,4,5,6, Yuting Liu 1,2,5,6, Xiaofei Liu 1,2,4,5,6, Chengxiang Xia 1,2,3,5,6, Tongjie Wang 1,2,5,6,Peiqing Zhou 1,2,3,5,6, Kaitao Wang 1,2,4,5,6, Yong Dong 1,2,5,6, Yuxuan Luo8, Xiangzhong Zhang8, Yuxian Guan 1,2,5,6, Yang Geng 1,2,4,5,6, Juan Du 1,2,3,5,6, Yangqiu Li 9, Yu Lan 9, Jiekai Chen 1,2,3,4,5,6, Bing Liu 7 and Jinyong Wang 1,2,3,4,5,6

1 State Key Laboratory of Experimental Hematology, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; 2Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou, China; 3University of Chinese Academy of Sciences, Beijing, China; 4Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Guangzhou, China; 5Guangdong Provincial Key Laboratory of Stem cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; 6Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; 7State Key Laboratory of Proteomics, Translational Medicine Center of Stem Cells, Fifth Medical Center, General Hospital of PLA, Beijing, China; 8Department of Hematology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China and 9Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
 Correspondence: Bing Liu (bingliu17@yahoo.com) or Jinyong Wang (wang_jinyong@gibh.ac.cn)These authors contributed equally: Rongqun Guo, Fangxiao Hu, Qitong Weng

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.


https://doi.org/10.1038/s41422-019-0251-7

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