Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis
Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis
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DOI：
10.1038/nm973
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发表时间：
2004-01-01
期刊：
影响因子：
82.9
通讯作者：
Rafii, S
中科院分区：
文献类型：
--
作者：
Avecilla, ST;Hattori, K;Rafii, S
参与造血祖细胞分化的分子途径尚不清楚。在这里，我们报道了趋化因子介导的巨核细胞祖细胞与正弦骨髓内皮细胞（BMECs）的相互作用促进了血小板生成素（TPO）不依赖的血小板产生。巨核细胞活性细胞因子，包括白细胞介素-6 （IL-6）和IL-11，在血小板减少性、TPO缺陷（Thpo(-/-)）或TPO受体缺陷（Mpl(-/-)）小鼠中不诱导血小板产生。相比之下，巨核细胞活性趋化因子，包括基质衍生因子-1 （SDF-1）和成纤维细胞生长因子-4 (FGF-4)，可以恢复Thpo（-/-）和Mpl（-/-）小鼠的血小板生成。FGF-4和SDF-1增强了血管细胞粘附分子-1 （VCAM-1）和极晚抗原-4 （VLA-4）介导的CXCR4（+）巨核细胞祖细胞向血管生态位的定位，促进了存活、成熟和血小板释放。在生理条件下和骨髓抑制后，血管生态位的破坏或巨核细胞运动的干扰会抑制血小板生成。骨髓抑制后，SDF-1和FGF-4可减少血小板减少。这些数据表明，TPO支持祖细胞扩增，而趋化因子介导的祖细胞与骨髓血管生态位的相互作用允许祖细胞迁移到一个允许和指导巨核细胞成熟和血小板生成的微环境。祖活性趋化因子提供了一个新的策略，以恢复造血在临床设置。
The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule- 1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.