Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2020,（1）
• 页码范围: 21-33
• 页数: 13页
• 语种: 英文
• DOI: 10.1038/s41422-019-0251-7

摘要

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-tohematopoietic transition and hematopoietic maturation stages in a PSC differentiation scheme (iRg-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 PSCsource.