Journal
CELL STEM CELL
Volume 6, Issue 3, Pages 251-264Publisher
CELL PRESS
DOI: 10.1016/j.stem.2010.02.001
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Funding
- Starr Stem Cell
- Kirschstein National Research Service
- Howard Hughes Medical Institute
- Ansary Stem Cell Institute
- Anbinder and Newmans Own Foundation
- National Heart Lung and Blood Institute [HL075234, HL097797]
- Qatar National Priorities
- Empire State Stem Cell Board
- New York State Department of Health [NYS C024180]
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Bone marrow endothelial cells (ECs) are essential for reconstitution of hematopoiesis, but their role in self-renewal of long-term hematopoietic stem cells (LT-HSCs) is unknown. We have developed angiogenic models to demonstrate that EC-derived angiocrine growth factors support in vitro self-renewal and in vivo repopulation of authentic LT-HSCs. In serum/cytokine-free cocultures, ECs, through direct cellular contact, stimulated incremental expansion of repopulating CD34(-)F1t3(-)cKit(+)Lineage(-)Sca1(+) LT-HSCs, which retained their self-renewal ability, as determined by single-cell and serial transplantation assays. Angiocrine expression of Notch ligands by ECs promoted proliferation and prevented exhaustion of LT-HSCs derived from wild-type, but not Notch1/Notch2-deficient, mice. In transgenic notch-reporter (TNR.Gfp) mice, regenerating TNR.Gfp(+) LT-HSCs were detected in cellular contact with sinusoidal ECs. Interference with angiocrine, but not perfusion, function of SECs impaired repopulation of TNR.Gfp(+) LT-HSCs. ECs establish an instructive vascular niche for clinical-scale expansion of LT-HSCs and a cellular platform to identify stem cellactive trophogens.
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