Endothelial Cells Are Essential for the Self-Renewal and Repopulation of Notch-Dependent Hematopoietic Stem Cells

被引:505
作者
Butler, Jason M. [1 ,2 ]
Nolan, Daniel J. [1 ,2 ]
Vertes, Eva L. [1 ,2 ]
Varnum-Finney, Barbara [4 ]
Kobayashi, Hideki [1 ,2 ]
Hooper, Andrea T. [1 ,2 ]
Seandel, Marco [1 ,2 ,3 ]
Shido, Koji [1 ,2 ]
White, Ian A. [1 ,2 ]
Kobayashi, Mariko [1 ,2 ]
Witte, Larry [5 ]
May, Chad [5 ]
Shawber, Carrie [6 ]
Kimura, Yuki [1 ,2 ]
Kitajewski, Jan [6 ,7 ]
Rosenwaks, Zev [4 ]
Bernstein, Irwin D. [8 ]
Rafii, Shahin [1 ,2 ]
机构
[1] Weill Cornell Med Coll, Dept Med Genet, Howard Hughes Med Inst, New York, NY 10065 USA
[2] Weill Cornell Med Coll, Ansary Stem Cell Inst, New York, NY 10065 USA
[3] Weill Cornell Med Coll, Dept Surg, New York, NY 10065 USA
[4] ImClone Syst Inc, New York, NY 10014 USA
[5] Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY 10065 USA
[6] Columbia Univ, Med Ctr, Dept OB GYN, New York, NY 10032 USA
[7] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA
[8] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA
关键词
BONE-MARROW NICHE; PROGENITOR CELLS; VASCULAR NICHE; TUMOR-GROWTH; IN-VITRO; EX-VIVO; GENE; EXPANSION; SURVIVAL; ANGIOGENESIS;
D O I
10.1016/j.stem.2010.02.001
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:251 / 264
页数:14
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