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Cell Res. 2019 Nov 15. doi: 10.1038/s41422-019-0251-7. [Epub ahead of print]

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

Guo R1,2,3,4,5, Hu F1,2,4,5, Weng Q1,2,3,4,5, Lv C1,2,4,5, Wu H1,2,4,5, Liu L1,2,6,4,5, Li Z7, Zeng Y7, Bai Z7, Zhang M1,2,6,4,5, Liu Y1,2,4,5, Liu X1,2,6,4,5, Xia C1,2,3,4,5, Wang T1,2,4,5, Zhou P1,2,3,4,5, Wang K1,2,6,4,5, Dong Y1,2,4,5, Luo Y8, Zhang X8, Guan Y1,2,4,5, Geng Y1,2,6,4,5, Du J1,2,3,4,5, Li Y9, Lan Y9, Chen J1,2,3,6,4,5, Liu B10, Wang J11,12,13,14,15,16.

Author information

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.
2
Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou, China.
3
University of Chinese Academy of Sciences, Beijing, China.
4
Guangdong Provincial Key Laboratory of Stem cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
5
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
6
Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Guangzhou, China.
7
State Key Laboratory of Proteomics, Translational Medicine Center of Stem Cells, Fifth Medical Center, General Hospital of PLA, Beijing, China.
8
Department of Hematology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
9
Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China.
10
State Key Laboratory of Proteomics, Translational Medicine Center of Stem Cells, Fifth Medical Center, General Hospital of PLA, Beijing, China. bingliu17@yahoo.com.
11
State Key Laboratory of Experimental Hematology, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. wang_jinyong@gibh.ac.cn.
12
Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou, China. wang_jinyong@gibh.ac.cn.
13
University of Chinese Academy of Sciences, Beijing, China. wang_jinyong@gibh.ac.cn.
14
Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Guangzhou, China. wang_jinyong@gibh.ac.cn.
15
Guangdong Provincial Key Laboratory of Stem cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. wang_jinyong@gibh.ac.cn.
16
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. wang_jinyong@gibh.ac.cn.

Abstract

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.

PMID:
31729468
DOI:
10.1038/s41422-019-0251-7

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