Developmental pathways that orchestrate the fleeting transition of endothelial cells into hematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to hematopoietic 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 hematopoietic 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 hematopoietic 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 signaling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable hematopoietic stem cells could aid treatment of hematological disorders.
Nature 2017;545:439-445 (25 May 2017); DOI: 10.1038/nature22326
Raphael Lis1, 2, Charles C. Karrasch1, 2, Michael G. Poulos1, 3, Balvir Kunar1, David Redmond4, Jose G. Barcia Duran1,Chaitanya R. Badwe1, William Schachterle1, Michael Ginsberg5, Jenny Xiang6, Arash Rafii Tabrizi7, Koji Shido1, Zev Rosenwaks2, Olivier Elemento4, Nancy A. Speck8, Jason M. Butler1, 3, Joseph M. Scandura9 & Shahin Rafii1
1Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA. 2Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, New York 10065, USA. 3Department of Surgery, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA. 4Institute for Computational Biomedicine & Institute for Precision Medicine, Weill Cornell Medicine, New York, New York 10065, USA. 5Angiocrine Bioscience, San Diego, California 92130, USA. 6Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10065, USA. 7Stem Cell and Microenvironment Laboratory, Department of Obstetrics and Gynecology, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, PO box 24144, Doha, Qatar. 8Abramson Family Cancer Research Institute, Institute for Regenerative Medicine and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 9Department of Medicine, Hematology-Oncology, Weill Cornell Medicine and the New York Presbyterian Hospital, New York, New York 10065, USA.