Hematopoiesis, the complex developmental process that forms blood components and replenishes the blood system, involves multiple intracellular and extracellular mechanisms. We previously demonstrated that lysophosphatidic acid (LPA), a lipid growth factor, has opposing regulatory effects on erythrocyte differentiation through activation of LPA receptors 2 and 3; yet the mechanisms underlying this process remain unclear. In this study, LPA₂ is observed that highly expressed in common myeloid progenitors (CMP) in murine myeloid cells, whereas the expression of LPA₃ displaces in megakaryocyte-erythroid progenitors (MEP) of later stage of myeloid differentiation. Therefore, we hypothesized that the switching expression of LPA₂ and LPA₃ determine the hematic homeostasis of mammalian megakaryocytic-erythroid lineage. In vitro colony-forming unit assays of murine progenitors reveal that LPA₂ agonist GRI reduces the erythroblast differentiation potential of CMP. In contrast, LPA₃ agonist OMPT increases the production of erythrocytes from megakaryocyte-erythrocyte progenitor cells (MEP). In addition, treatment with GRI reduces the erythroid, CMP, and MEP populations in mice, indicating that LPA₂ predominantly inhibits myeloid differentiation at an early stage. In contrast, activation of LPA₃ increases the production of terminally differentiated erythroid cells through activation of erythropoietic transcriptional factor. We also demonstrate that the LPA₃ signaling is essential for restoration of phenylhydrazine (PHZ)-induced acute hemolytic anemia in mice and correlates to erythropoiesis impairment of Hutchinson-Gilford progeria Symptom (HGPS) premature aging expressed K562 model. Our results reveal the distinct roles of LPA₂ and LPA₃ at different stages of hematopoiesis in vivo, providing potentiated therapeutic strategies of anemia treatment.

造血是形成血液成分并补充血液系统的复杂发育过程，涉及多种细胞内和细胞外机制。我们以前证明溶血磷脂酸（LPA），一种脂质生长因子，通过激活LPA受体2和3对红细胞的分化具有相反的调节作用。但是，该过程的机制尚不清楚。在这项研究中，观察到LPA ₂在鼠髓样细胞中在常见的髓样祖细胞（CMP）中高表达，而LPA ₃的表达在髓样细胞分化后期的巨核细胞-类红细胞祖细胞（MEP）中取代。因此，我们假设LPA ₂和LPA ₃的转换表达确定哺乳动物巨核细胞-红系血统的血液稳态。小鼠祖细胞的体外菌落形成单位测定显示，LPA ₂激动剂GRI降低了CMP的成红细胞分化潜能。相反，LPA ₃激动剂OMPT增加了巨核细胞-红细胞祖细胞（MEP）产生的红细胞。此外，用GRI处理可减少小鼠中的类红细胞，CMP和MEP群体，这表明LPA ₂在早期主要抑制了髓样分化。相反，激活LPA ₃通过激活促红细胞生成因子，增加终末分化红系细胞的产量。我们还证明，LPA ₃信号对于苯肼（PHZ）诱导的小鼠急性溶血性贫血的恢复至关重要，并且与Hutchinson-Gilford早衰症状（HGPS）早衰表达的K562模型的红细胞生成障碍相关。我们的结果揭示了LPA ₂和LPA ₃在体内造血不同阶段的独特作用，提供了贫血治疗的有效治疗策略。