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Nature
05 25, 2017;545 (7655): 439-445.

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
  1. Raphael Lis: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  2. Charles C Karrasch: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  3. Michael G Poulos: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  4. Balvir Kunar: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  5. David Redmond: Institute for Computational Biomedicine &Institute for Precision Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  6. Jose G Barcia Duran: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  7. Chaitanya R Badwe: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  8. William Schachterle: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  9. Michael Ginsberg: Angiocrine Bioscience, San Diego, California 92130, USA.
  10. Jenny Xiang: Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10065, USA.
  11. 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.
  12. Koji Shido: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  13. Zev Rosenwaks: Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, New York 10065, USA.
  14. Olivier Elemento: Institute for Computational Biomedicine &Institute for Precision Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  15. 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.
  16. Jason M Butler: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
  17. Joseph M Scandura: Department of Medicine, Hematology-Oncology, Weill Cornell Medicine and the New York Presbyterian Hospital, New York, New York 10065, USA.
  18. Shahin Rafii: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
PMID: 28514438 DOI: 10.1038/nature22326

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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Grants

  1. R01 HL133021/NHLBI NIH HHS
  2. R01 CA204308/NCI NIH HHS
  3. HL128158/NIH HHS
  4. U01 HL099997/NHLBI NIH HHS
  5. R01 HL115128/NHLBI NIH HHS
  6. R01 HL091724/NHLBI NIH HHS
  7. HL099997/NIH HHS
  8. HL133021/NIH HHS
  9. U54 CA163167/NCI NIH HHS
  10. R01 HL128158/NHLBI NIH HHS
  11. R01 DK095039/NIDDK NIH HHS
  12. HL119872/NIH HHS
  13. R01 HL097797/NHLBI NIH HHS
  14. NIH-R01 HL091724/NIH HHS
  15. T32 HD060600/NICHD NIH HHS
  16. R01 HL119872/NHLBI NIH HHS
  17. HL115128/NIH HHS

MeSH Term

Adaptive Immunity
Aging
Animals
Cell Differentiation
Cell Line
Cell Lineage
Cell Self Renewal
Cellular Reprogramming
Clone Cells
Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins
Endothelial Cells
Endothelium
Hematopoiesis
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Humans
Male
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-fos
T-Lymphocytes
Trans-Activators
Transcription Factors
Transcriptome

Chemicals

Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins
FOSB protein, human
GFI1 protein, human
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-fos
RUNX1 protein, human
Trans-Activators
Transcription Factors
proto-oncogene protein Spi-1
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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