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

Jui Chung Chiang, Wei Min Chen, Kuan Hung Lin, Kai Hsia, Ya Hsuan Ho, Yueh Chien Lin, Tang Long Shen, Jen Her Lu, Shih Kuo Chen, Chao Ling Yao, Benjamin P.C. Chen, Hsinyu Lee

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number158818
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1866
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate
  • Anemia
  • Erythropoiesis
  • GRI compound 977143
  • Lysophosphatidic acid
  • Lysophosphatidic acid receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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