[PDF][PDF] Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells

JM Butler, DJ Nolan, EL Vertes, B Varnum-Finney… - Cell stem cell, 2010 - cell.com
JM Butler, DJ Nolan, EL Vertes, B Varnum-Finney, H Kobayashi, AT Hooper, M Seandel…
Cell stem cell, 2010cell.com
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− Flt3− cKit+ Lineage− Sca1+ LT-HSCs, which retained …
Summary
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 CD34Flt3cKit+LineageSca1+ 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 cell-active trophogens.
cell.com