Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

• Published in: Cell research 2020-01, Vol.30 (1), p.21-33
• Main Authors: Guo, Rongqun, Hu, Fangxiao, Weng, Qitong, Lv, Cui, Wu, Hongling, Liu, Lijuan, Li, Zongcheng, Zeng, Yang, Bai, Zhijie, Zhang, Mengyun, Liu, Yuting, Liu, Xiaofei, Xia, Chengxiang, Wang, Tongjie, Zhou, Peiqing, Wang, Kaitao, Dong, Yong, Luo, Yuxuan, Zhang, Xiangzhong, Guan, Yuxian, Geng, Yang, Du, Juan, Li, Yangqiu, Lan, Yu, Chen, Jiekai, Liu, Bing, Wang, Jinyong
• Format: Article
• Language: English
• Subjects: 13; 13/100; 631/250; 631/532/2064; Animals; Biomedical and Life Sciences; Cell Biology; Cells, Cultured; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Embryonic Stem Cells - physiology; Endothelial cells; Gene expression; Genetic modification; Graft Rejection - immunology; Hemopoiesis; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Homing; Immunodeficiency; Immunosurveillance; In vivo methods and tests; Life Sciences; Lymphocytes; Lymphocytes T; Lymphopoiesis; Lymphopoiesis - genetics; Maturation; Mice; Neoplasms, Experimental - immunology; Organs; Pluripotency; Pluripotent Stem Cells - physiology; Receptors, Antigen, T-Cell, alpha-beta - chemistry; Regenerative medicine; Runx1 protein; Skin Transplantation; Stem cell transplantation; Stem cells; T-Lymphocytes - immunology; Thymus; Transcription factors; Tumor cells; Tumors; Windows (intervals)
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/s41422-019-0251-7

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.