Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells.
Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells.
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DOI：
10.1016/j.stem.2009.01.006
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发表时间：
2009-03-06
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：
Hooper AT;Butler JM;Nolan DJ;Kranz A;Iida K;Kobayashi M;Kopp HG;Shido K;Petit I;Yanger K;James D;Witte L;Zhu Z;Wu Y;Pytowski B;Rosenwaks Z;Mittal V;Sato TN;Rafii S
骨髓（BM）窦内皮细胞（SEC）再生的表型属性和分子决定因素及其对造血的贡献尚不清楚。我们发现，骨髓抑制后，VEGFR2激活促进了消退的SEC的重组，重建造血干细胞和祖细胞（HSPC）。VEGFR2和VEGFR3的表达仅限于BM脉管系统，划分出VEGFR2+VEGFR3+Sca1− SEC和VEGFR2+VEGFR3−Sca1+小动脉的连续网络。虽然化疗（5FU）和亚致死辐射（650拉德）诱导轻微的SEC消退，致死辐射（950拉德）诱导严重的SEC消退，需要骨髓移植（BMT）再生。成年小鼠中VEGFR2的条件性缺失阻断了亚致死剂量照射动物中SEC的再生，阻止了造血重建。在用BMT拯救的致死性照射的野生型小鼠中抑制VEGFR2信号传导严重损害SEC重建，阻止HSPC的植入和重建。因此，VEGFR2的激活对于VEGFR3+Sca1− SEC的再生至关重要，而VEGFR3+Sca1− SEC对于HSPC的植入和恢复以及造血至关重要。
The phenotypic attributes and molecular determinants for the regeneration of bone marrow (BM) sinusoidal endothelial cells (SECs) and their contribution to hematopoiesis are unknown. We show that after myelosuppression VEGFR2 activation promotes reassembly of regressed SECs, reconstituting hematopoietic stem and progenitor cells (HSPCs). VEGFR2 and VEGFR3 expression are restricted to BM vasculature, demarcating a continuous network of VEGFR2+VEGFR3+Sca1− SECs and VEGFR2+VEGFR3−Sca1+ arterioles. While chemotherapy (5FU) and sublethal irradiation (650 rad) induce minor SEC regression, lethal irradiation (950 rad) induces severe regression of SECs requiring BM transplantation (BMT) for regeneration. Conditional deletion of VEGFR2 in adult mice blocks regeneration of SECs in sublethally irradiated animals, preventing hematopoietic reconstitution. Inhibition of VEGFR2 signaling in lethally irradiated wild type mice rescued with BMT severely impairs SEC reconstruction, preventing engraftment and reconstitution of HSPCs. Therefore, activation of VEGFR2 is critical for regeneration of VEGFR3+Sca1− SECs that are essential for engraftment and restoration of HSPCs and hematopoiesis.
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DOI：
10.1073/pnas.94.2.663
发表时间：
1997-01-21
影响因子：
11.1
作者：
Mohle, R;Green, D;Rafii, S
通讯作者：
Rafii, S
影响因子：
30.5
作者：
Sapoznikov, Anita;Pewzner-Jung, Yael;Jung, Steffen
通讯作者：
Jung, Steffen
影响因子：
64.5
作者：
Kiel, MJ;Yilmaz, ÖH;Morrison, SJ
通讯作者：
Morrison, SJ
影响因子：
15.9
作者：
Kopp, Hans-Georg;Hooper, Andrea T.;Rafii, Shahin
通讯作者：
Rafii, Shahin
影响因子：
20.3
作者：
Naiyer, AJ;Jo, DY;Rafii, S
通讯作者：
Rafii, S