Lysophosphatidic acid receptors 2 and 3 regulate erythropoiesis at different hematopoietic stages

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.