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 and Shahin Rafii ()
Additional contact information
Raphael Lis: Ansary Stem Cell Institute, Weill Cornell Medicine
Charles C. Karrasch: Ansary Stem Cell Institute, Weill Cornell Medicine
Michael G. Poulos: Ansary Stem Cell Institute, Weill Cornell Medicine
Balvir Kunar: Ansary Stem Cell Institute, Weill Cornell Medicine
David Redmond: Institute for Computational Biomedicine & Institute for Precision Medicine, Weill Cornell Medicine
Jose G. Barcia Duran: Ansary Stem Cell Institute, Weill Cornell Medicine
Chaitanya R. Badwe: Ansary Stem Cell Institute, Weill Cornell Medicine
William Schachterle: Ansary Stem Cell Institute, Weill Cornell Medicine
Michael Ginsberg: Angiocrine Bioscience
Jenny Xiang: Genomics Resources Core Facility, Weill Cornell Medicine
Arash Rafii Tabrizi: Stem Cell and Microenvironment Laboratory, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation
Koji Shido: Ansary Stem Cell Institute, Weill Cornell Medicine
Zev Rosenwaks: Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine
Olivier Elemento: Institute for Computational Biomedicine & Institute for Precision Medicine, Weill Cornell Medicine
Nancy A. Speck: Abramson Family Cancer Research Institute, University of Pennsylvania
Jason M. Butler: Ansary Stem Cell Institute, Weill Cornell Medicine
Joseph M. Scandura: Hematology-Oncology, Weill Cornell Medicine and the New York Presbyterian Hospital
Shahin Rafii: Ansary Stem Cell Institute, Weill Cornell Medicine

Nature, 2017, vol. 545, issue 7655, 439-445

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22326

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