Erythropoietin is a major regulator of thrombopoiesis in thrombopoietin-dependent and -independent contexts
Erythropoietin is a major regulator of thrombopoiesis in thrombopoietin-dependent and -independent contexts
复制标题
DOI：
10.1016/j.exphem.2020.07.006
复制
发表时间：
2020-08-01
影响因子：
2.6
通讯作者：
Abina, Amine M.
中科院分区：
文献类型：
--
作者：
Hacein-Bey-Abina, Salima;Estienne, Machadiya;Abina, Amine M.
血小板生成素（TPO）通过激活其同源受体Mpl，是血小板产生的主要调节剂。然而，在TPO和mpl功能丧失（LOF）小鼠中观察到的残留血小板表明，在血小板产生中存在TPO以外的其他因素。由于促红细胞生成素（EPO）在体外表现出与其他早期作用细胞因子相关的巨核细胞潜能，以及体内血小板激活活性，我们试图研究其在这种情况下的作用。在这里，我们使用多个LOF模型来解读EPO和TPO在调节TPO-LOF和Mpl-LOF小鼠血小板生成和野生型小鼠血小板大小异质性中的相互作用。在缺乏TPO-Mpl通路的情况下，我们首先确定EPO是主要的血栓形成因子。通过对几种小鼠模型的研究，我们发现EPO-EPO受体通路作用于晚期巨核生成，并负责大尺寸血小板的产生，而TPO-Mpl通路促进小尺寸血小板的产生。根据我们的数据，促生成素可能用于先天性无核细胞生成的血小板减少支持治疗。此外，由于大血小板倾斜分布是动脉粥样硬化血栓形成的独立危险因素和不良预后指标，EPO在大血小板生成中的作用的表征，如果在人类中得到证实，可能为理解EPO诱导的血小板在动脉粥样硬化血栓形成中的作用开辟新的视角。(c) 2020 ISEH -血液学和干细胞学会。Elsevier Inc.出版。版权所有。
Thrombopoietin (TPO), through activation of its cognate receptor Mpl, is the major regulator of platelet production. However, residual platelets observed in TPO-and Mpl-loss-of-functi on (LOF) mice suggest the existence of an additional factor to TPO in platelet production. As erythropoietin (EPO) exhibited both in vitro megakaryocytic potential, in association with other early-acting cytokines, and in vivo platelet activa-tion activity, we sought to investigate its role in this setting. Here, we used multiple LOF models to decipher the reciprocal role of EPO and TPO in the regulation of plate-let production in TPO-LOF and Mpl-LOF mice and of platelet size heterogeneity in wild-type mice. We first identified EPO as the major thrombopoietic factor in the absence of the TPO-Mpl pathway. Based on the study of several mouse models we found that the EPO-EPO receptor pathway acts on late-stage megakaryopoiesis and is responsible for large-sized platelet production, while the TPO-Mpl pathway promotes small-sized platelet production. On the basis of our data, EPO might be used for thrombocytopenia supportive therapy in congenital amegakaryocytopoiesis. Further-more, as a distribution skewed toward large platelets is an independent risk factor and a poor prognosis indicator in atherothrombosis, the characterization of EPO's role in the production of large-sized platelets, if confirmed in humans, may open new perspec-tives in the understanding of the role of EPO-induced platelets in atherothrombosis. (c) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.