SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury
SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury
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DOI：
10.1182/blood-2014-01-547638
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发表时间：
2014-07-10
期刊：
影响因子：
20.3
通讯作者：
Palis, James
中科院分区：
文献类型：
--
作者：
Niswander, Lisa M.;Fegan, Katherine H.;Palis, James
骨髓中巨核细胞（MK）的发育在空间上从骨内膜龛（促进MK祖细胞增殖）发展到窦状隙血管龛（终末成熟和血小板生成的部位）。趋化因子基质细胞衍生因子-1（SDF-1）通过CXCR 4进行信号传导，参与MK向窦状血管的成熟趋化性。在这里，我们证明了静脉注射SDF-1和稳定内源性SDF-1都能迅速增加MK-血管系统的结合和血小板生成，而MK数量没有变化。在辐射损伤的背景下，我们发现骨髓SDF-1分布的动态波动与MK生态位占用的变化在空间和时间上相关。改变的SDF-1梯度的稳定直接影响MK位置。重要的是，这些SDF-1介导的变化对血小板产生具有功能性后果，因为MK远离脉管系统的运动减少了循环血小板，而MK与脉管系统的结合增加了循环血小板。最后，我们证明了SDF-1梯度的操作可以改善辐射诱导的血小板减少症的方式添加剂与早期TPO治疗。总之，我们的数据支持SDF-1调节骨髓中MK的空间分布并因此调节循环血小板数量的概念。MK谱系的微环境调节的这一知识可能会导致血小板减少症的治疗策略的改善。
Megakaryocyte (MK) development in the bone marrow progresses spatially from the endosteal niche, which promotes MK progenitor proliferation, to the sinusoidal vascular niche, the site of terminal maturation and thrombopoiesis. The chemokine stromal cell-derived factor-1 (SDF-1), signaling through CXCR4, is implicated in the maturational chemotaxis of MKs toward sinusoidal vessels. Here, we demonstrate that both IV administration of SDF-1 and stabilization of endogenous SDF-1 acutely increase MK-vasculature association and thrombopoiesis with no change in MK number. In the setting of radiation injury, we find dynamic fluctuations in marrow SDF-1 distribution that spatially and temporally correlate with variations in MK niche occupancy. Stabilization of altered SDF-1 gradients directly affects MK location. Importantly, these SDF-1-mediated changes have functional consequences for platelet production, as the movement of MKs away from the vasculature decreases circulating platelets, while MK association with the vasculature increases circulating platelets. Finally, we demonstrate that manipulation of SDF-1 gradients can improve radiation-induced thrombocytopenia in a manner additive with earlier TPO treatment. Taken together, our data support the concept that SDF-1 regulates the spatial distribution of MKs in the marrow and consequently circulating platelet numbers. This knowledge of the microenvironmental regulation of the MK lineage could lead to improved therapeutic strategies for thrombocytopenia.