Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells.
Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells.
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DOI：
10.1016/j.stem.2010.02.001
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发表时间：
2010-03-05
期刊：
影响因子：
23.9
通讯作者：
Rafii S
中科院分区：
文献类型：
--
作者：
Butler JM;Nolan DJ;Vertes EL;Varnum-Finney B;Kobayashi H;Hooper AT;Seandel M;Shido K;White IA;Kobayashi M;Witte L;May C;Shawber C;Kimura Y;Kitajewski J;Rosenwaks Z;Bernstein ID;Rafii S
骨髓内皮细胞（ECs）对造血重建至关重要，但其在长期造血干细胞（lt - hsc）自我更新中的作用尚不清楚。我们已经开发了血管生成模型，以证明ec衍生的血管分泌生长因子支持真实lt - hsc的体外自我更新和体内再生。在无血清/细胞因子的共培养中，ec通过直接细胞接触刺激了CD34 - Flt3 - cKit+Lineage - Sca1+ lt - hsc的增殖，通过单细胞和系列移植实验确定了其自我更新能力。ECs表达notch配体的血管分泌可促进野生型小鼠lt - hsc的增殖并阻止其衰竭，但对Notch1/Notch2缺陷小鼠没有作用。在转基因缺口报告基因（TNR. gfp）小鼠中，再生TNR。Gfp+ lt - hsc与正弦型内皮细胞接触，干扰内皮细胞的血管分泌，但不干扰灌注功能，损害TNR的再生。Gfp + LT-HSCs。内皮细胞为lt -造血干细胞的临床规模扩张建立了指导性血管生态位，并为鉴定干细胞活性滋养细胞提供了细胞平台。
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 co-cultures, 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 and interfering 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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