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1875-9777632010Mar05Cell stem cellCell Stem CellEndothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells.251264251-6410.1016/j.stem.2010.02.001Bone 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 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.2010 Elsevier Inc. All rights reserved.ButlerJason MJMHoward Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.NolanDaniel JDJVertesEva LELVarnum-FinneyBarbaraBKobayashiHidekiHHooperAndrea TATSeandelMarcoMShidoKojiKWhiteIan AIAKobayashiMarikoMWitteLarryLMayChadCShawberCarrieCKimuraYukiYKitajewskiJanJRosenwaksZevZBernsteinIrwin DIDRafiiShahinSengRC1 AI080309-01AINIAID NIH HHSUnited StatesP01 HL059312-090006HLNHLBI NIH HHSUnited StatesR01 HL097797-03HLNHLBI NIH HHSUnited StatesP50 HL084936HLNHLBI NIH HHSUnited StatesP01 HL059312-100006HLNHLBI NIH HHSUnited StatesR01 HL097797-01HLNHLBI NIH HHSUnited StatesU01 HL066952-020002HLNHLBI NIH HHSUnited StatesRC1 AI080309AINIAID NIH HHSUnited StatesP01 HL059312HLNHLBI NIH HHSUnited StatesU01 HL066952-040002HLNHLBI NIH HHSUnited StatesP01 HL059312-080006HLNHLBI NIH HHSUnited StatesHL075234HLNHLBI NIH HHSUnited StatesR21 HL083222-01HLNHLBI NIH HHSUnited StatesU01 HL066952HLNHLBI NIH HHSUnited StatesU01 HL066952-030002HLNHLBI NIH HHSUnited StatesP50 HL084936-010003HLNHLBI NIH HHSUnited StatesR21 HL083222-02HLNHLBI NIH HHSUnited StatesP01 HL067839HLNHLBI NIH HHSUnited StatesP50 HL084936-030003HLNHLBI NIH HHSUnited StatesR01 HL097797-02HLNHLBI NIH HHSUnited StatesR01 HL097797HLNHLBI NIH HHSUnited StatesP50 HL084936-020003HLNHLBI NIH HHSUnited StatesP01 HL059312-060006HLNHLBI NIH HHSUnited StatesP01 HL084205HLNHLBI NIH HHSUnited StatesHL097797HLNHLBI NIH HHSUnited StatesP01 HL067839-050004HLNHLBI NIH HHSUnited StatesP01 HL059312-070006HLNHLBI NIH HHSUnited StatesP50 HL084936-040003HLNHLBI NIH HHSUnited StatesU01 HL066952-050002HLNHLBI NIH HHSUnited StatesU01 HL066952-010002HLNHLBI NIH HHSUnited StatesR01 CA136673CANCI NIH HHSUnited StatesHHMIHoward Hughes Medical InstituteUnited StatesP01 HL067839-040004HLNHLBI NIH HHSUnited StatesR21 HL083222HLNHLBI NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't
United StatesCell Stem Cell1013114721875-97770Culture Media, Conditioned0Ligands0Notch1 protein, mouse0Notch2 protein, mouse0Receptor, Notch10Receptor, Notch2IMAnimalsCell CommunicationCell LineageCell ProliferationCells, CulturedCoculture TechniquesCulture Media, ConditionedEndothelial CellscytologymetabolismHematopoietic Stem CellscytologymetabolismLigandsMiceMice, KnockoutReceptor, Notch1deficiencymetabolismReceptor, Notch2deficiencymetabolismSignal Transduction
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Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. | LitMetric

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 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.

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