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31729468
Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors.

Cell Res, 2020/01;30(1):21-33.

Guo R[1, 2, 3, 4, 5], Hu F[1, 2, 4, 5], Weng Q[1, 2, 3, 4, 5], Lv C[1, 2, 4, 5], Wu H[1, 2, 4, 5], Liu L[1, 2, 6, 4, 5], Li Z[7], Zeng Y[7], Bai Z[7], Zhang M[1, 2, 6, 4, 5], Liu Y[1, 2, 4, 5], Liu X[1, 2, 6, 4, 5], Xia C[1, 2, 3, 4, 5], Wang T[1, 2, 4, 5], Zhou P[1, 2, 3, 4, 5], Wang K[1, 2, 6, 4, 5], Dong Y[1, 2, 4, 5], Luo Y[8], Zhang X[8], Guan Y[1, 2, 4, 5], Geng Y[1, 2, 6, 4, 5], Du J[1, 2, 3, 4, 5], Li Y[9], Lan Y[9], Chen J[1, 2, 3, 6, 4, 5], Liu B[10], Wang J[11, 12, 13, 14, 15, 16]

Affiliations

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

Impact factor: 46.297

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.
MeSH terms
Animals; Cells, Cultured; Core Binding Factor Alpha 2 Subunit; Embryonic Stem Cells; Graft Rejection; Homeodomain Proteins; Lymphopoiesis; Mice; Neoplasms, Experimental; Pluripotent Stem Cells; Receptors, Antigen, T-Cell, alpha-beta; Skin Transplantation; T-Lymphocytes
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