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

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.

SUBMITTER: Chiang JC

PROVIDER: S-EPMC7683362 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Chiang Jui-Chung JC Chen Wei-Min WM Lin Kuan-Hung KH Hsia Kai K Ho Ya-Hsuan YH Lin Yueh-Chien YC Shen Tang-Long TL Lu Jen-Her JH Chen Shih-Kuo SK Yao Chao-Ling CL Chen Benjamin P C BPC Lee Hsinyu H

Biochimica et biophysica acta. Molecular and cell biology of lipids 20201006 1

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, LPA<sub>2</sub> is observed that highly expressed in common m ...[more]

PMID: 33035680

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Project description:BackgroundLysophosphatidic acid (LPA) acts through the cell surface G protein-coupled receptors, LPA1, LPA2, or LPA3, to elicit a wide range of cellular responses. It is present at high levels in intraperitoneal effusions of human ovarian cancer increasing cell survival, proliferation, and motility as well as stimulating production of neovascularizing factors. LPA2 and LPA3 and enzymes regulating the production and degradation of LPA are aberrantly expressed by ovarian cancer cells, but the consequences of these expression changes in ovarian cancer cells were unknown.MethodsExpression of LPA1, LPA2, or LPA3 was inhibited or increased in ovarian cancer cells using small interfering RNAs (siRNAs) and lentivirus constructs, respectively. We measured the effects of changes in LPA receptor expression on cell proliferation (by crystal violet staining), cell motility and invasion (using Boyden chambers), and cytokines (interleukin 6 [IL-6], interleukin 8 [IL-8], and vascular endothelial growth factor [VEGF]) production by enzyme-linked immunosorbent assay. The role of LPA receptors in tumor growth, ascites formation, and cytokine production was assessed in a mouse xenograft model. All statistical tests were two-sided.ResultsSKOV-3 cells with increased expression of LPA receptors showed increased invasiveness, whereas siRNA knockdown inhibited both migration (P < .001, Student t test) and invasion. Knockdown of the LPA2 or LPA3 receptors inhibited the production of IL-6, IL-8, and VEGF in SKOV-3 and OVCAR-3 cells. SKOV-3 xenografts expressing LPA receptors formed primary tumors of increased size and increased ascites volume. Invasive tumors in the peritoneal cavity occurred in 75% (n = 4) of mice injected with LPA1 expressing SKOV-3 and 80% (n = 5) of mice injected with LPA2 or LPA3 expressing SKOV-3 cells. Metastatic tumors expressing LPA1, LPA2, and LPA3 were identified in the liver, kidney, and pancreas; tumors expressing LPA2 and LPA3 were detected in skeletal muscle; and tumors expressing LPA2 were also found in the cervical lymph node and heart. The percent survival of mice with tumors expressing LPA2 or LPA3 was reduced in comparison with animals with tumors expressing beta-galactosidase.ConclusionsExpression of LPA2 or LPA3 during ovarian carcinogenesis contributes to ovarian cancer aggressiveness, suggesting that the targeting of LPA production and action may have potential for the treatment of ovarian cancer.

Dataset Information

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

Publications

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

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