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Nature. 2017 May 25;545(7655):439-445. doi: 10.1038/nature22326. Epub 2017 May 17.

Conversion of adult endothelium to immunocompetent haematopoietic stem cells.

Author information

1
Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
2
Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, New York 10065, USA.
3
Department of Surgery, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
4
Institute for Computational Biomedicine &Institute for Precision Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
5
Angiocrine Bioscience, San Diego, California 92130, USA.
6
Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10065, USA.
7
Stem Cell and Microenvironment Laboratory, Department of Obstetrics and Gynecology, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, PO box 24144, Doha, Qatar.
8
Abramson Family Cancer Research Institute, Institute for Regenerative Medicine and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
9
Department of Medicine, Hematology-Oncology, Weill Cornell Medicine and the New York Presbyterian Hospital, New York, New York 10065, USA.

Abstract

Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse 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. The induction phase (days 0-8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8-20), RUNX1+ FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20-28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGFβ and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.

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PMID:
28514438
PMCID:
PMC5794215
DOI:
10.1038/nature22326
[Indexed for MEDLINE]
Free PMC Article

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