School of Pharmacy (X.F., X.Y.) and Division of Hematology, Department of Medicine and Therapeutics (R.S.M.W.), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; and Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York (W.K.).
School of Pharmacy (X.F., X.Y.) and Division of Hematology, Department of Medicine and Therapeutics (R.S.M.W.), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; and Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York (W.K.)
J Pharmacol Exp Ther. 2022 Jul;382(1):31-43. doi: 10.1124/jpet.122.001130. Epub 2022 Apr 30.
Erythropoietin (EPO) and thrombopoietin (TPO) have long been known to promote erythropoiesis and megakaryopoiesis, respectively. However, the fate-changing role of EPO and TPO on megakaryocyte-erythroid progenitors (MEPs) to develop along the erythroid versus megakaryocyte lineage remains unclear. We have previously shown that EPO may have a fate-changing role because EPO treatment could induce progenitor cells depletion and result in EPO resistance. Therefore, we hypothesize that a combination of romiplostim, a TPO receptor agonist that could stimulate the expansion of progenitors, with EPO can treat EPO resistance. Using rats with anemia due to chronic kidney disease, we demonstrated that romiplostim synergized with EPO to promote red blood cells production whereas EPO inhibited platelet production in a dose-dependent manner to reduce the risk of thrombosis. Corroborating findings from in vivo, in vitro experiments demonstrated that romiplostim expanded hematopoietic stem cells and stimulated megakaryopoiesis whereas EPO drove the progenitors toward an erythroid fate. We further developed a novel pharmacokinetic-pharmacodynamic model to quantify the effects of EPO and romiplostim on megakaryopoiesis and erythropoiesis simultaneously. The modeling results demonstrated that EPO increased the differentiation rate of MEPs into burst-forming unit-erythroid cells up to 22-fold, indicating that the slight increase of MEPs induced by romiplostim could be further amplified and recruited by EPO to promote erythropoiesis. The data herein support that romiplostim in combination with EPO can treat EPO resistance. SIGNIFICANCE STATEMENT: This study clarified that erythropoietin (EPO) drives the fate of megakaryocyte-erythroid progenitors (MEPs) toward the erythroid lineage, thus reducing their megakaryocyte (MK) lineage commitment, whereas romiplostim, a thrombopoietin receptor agonist, stimulates megakaryopoiesis through the MK-committed progenitor and MEP bifurcation pathways simultaneously. These findings support an innovative combination of romiplostim and EPO to treat EPO-resistant anemia because the combination therapy further promotes erythropoiesis compared to EPO monotherapy and inhibits platelet production compared to romiplostim monotherapy.
促红细胞生成素（EPO）和血小板生成素（TPO）长期以来一直被认为分别促进红细胞生成和巨核细胞生成。然而，EPO 和 TPO 对巨核细胞-红细胞祖细胞（MEP）的命运改变作用，使其沿着红细胞与巨核细胞谱系发展仍不清楚。我们之前的研究表明，EPO 可能具有改变命运的作用，因为 EPO 治疗会诱导祖细胞耗竭，并导致 EPO 抵抗。因此，我们假设 romiplostim（一种可刺激祖细胞扩增的 TPO 受体激动剂）与 EPO 的联合治疗可以治疗 EPO 抵抗。我们使用因慢性肾脏病导致贫血的大鼠，证明 romiplostim 与 EPO 协同作用可促进红细胞生成，而 EPO 则以剂量依赖性方式抑制血小板生成，以降低血栓形成的风险。体内、体外实验的验证结果表明，romiplostim 扩增了造血干细胞并刺激了巨核细胞生成，而 EPO 则促使祖细胞向红细胞命运发展。我们进一步开发了一种新的药代动力学-药效学模型，以定量评估 EPO 和 romiplostim 对巨核细胞生成和红细胞生成的影响。建模结果表明，EPO 将 MEP 分化为爆式形成单位-红细胞的速率提高了 22 倍，表明 romiplostim 诱导的 MEP 轻微增加可被 EPO 进一步放大并募集，以促进红细胞生成。这些数据支持 romiplostim 与 EPO 联合治疗 EPO 抵抗。意义：本研究阐明了促红细胞生成素（EPO）促使巨核细胞-红细胞祖细胞（MEP）向红细胞谱系发展，从而减少其向巨核细胞（MK）谱系的定向分化，而血小板生成素受体激动剂 romiplostim 通过 MK 定向祖细胞和 MEP 分叉途径同时刺激巨核细胞生成。这些发现支持 romiplostim 与 EPO 的联合治疗，因为与 EPO 单药治疗相比，联合治疗进一步促进了红细胞生成，与 romiplostim 单药治疗相比，抑制了血小板生成。
