Conversion of adult endothelium to immunocompetent haematopoietic stem cells.
Raphael Lis, Charles C Karrasch, Michael G Poulos, Balvir Kunar, David Redmond, Jose G Barcia Duran, Chaitanya R Badwe, William Schachterle, Michael Ginsberg, Jenny Xiang, Arash Rafii Tabrizi, Koji Shido, Zev Rosenwaks, Olivier Elemento, Nancy A Speck, Jason M Butler, Joseph M Scandura, Shahin Rafii
Author Information
Raphael Lis: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Charles C Karrasch: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Michael G Poulos: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Balvir Kunar: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
David Redmond: Institute for Computational Biomedicine &Institute for Precision Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Jose G Barcia Duran: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Chaitanya R Badwe: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
William Schachterle: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Michael Ginsberg: Angiocrine Bioscience, San Diego, California 92130, USA.
Jenny Xiang: Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10065, USA.
Arash Rafii Tabrizi: Stem Cell and Microenvironment Laboratory, Department of Obstetrics and Gynecology, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, PO box 24144, Doha, Qatar.
Koji Shido: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Zev Rosenwaks: Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, New York 10065, USA.
Olivier Elemento: Institute for Computational Biomedicine &Institute for Precision Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Nancy A Speck: Abramson Family Cancer Research Institute, Institute for Regenerative Medicine and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Jason M Butler: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Joseph M Scandura: Department of Medicine, Hematology-Oncology, Weill Cornell Medicine and the New York Presbyterian Hospital, New York, New York 10065, USA.
Shahin Rafii: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
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.
