We devised a tractable approach to fully reprogram adult human endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors.

rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to adult haematopoietic stem cells, and can be used for clonal engraftment with serial primary and secondary multi-lineage reconstitution. rEC-HSCs give rise to fully mature lymphoid CD4+ and CD8+ T cells. These T cells exhibit a diverse TCR repertoire and are endowed with antigen-dependent adaptive immune function.

These T cells are capable of anti-tumor response, and are amenable to chimeric antigen receptor (CAR) gene editing without losing their T lymphoid properties.

Our combined approach of transcription factor and niche-mediated cell fate conversion produces haematopoietic stem cells from adult human endothelium and holds promise for modelling hematologic disease in humanized mice and for immune-therapeutic strategies in malignant blood disorders.

Disclosures

No relevant conflicts of interest to declare.

Topics:
antigens, chimeric antigen receptors, endothelium, gene editing, hematological diseases, hematopoietic stem cells, neoplasms, pu-1 protein, transcription factor, t-lymphocytes

Author notes

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Asterisk with author names denotes non-ASH members.

© 2017 by The American Society of Hematology
2017
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