Lysophosphatidic acid receptors 2 and 3 regulate erythropoiesis at different hematopoietic stages
2021
Chiang, Jui-Chung | Chen, Wei-Min | Lin, Kuan-Hung | Hsia, Kai | Ho, Ya-Hsuan | Lin, Yueh-Chien | Shen, Tang-Long | Lu, Jen-Her | Chen, Shih-Kuo | Yao, Chao-Ling | Chen, Benjamin P.C. | Lee, Hsinyu
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.
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