Pharmacological activation of LPA receptors regulates mammalian erythro-megakaryocytic differentiation in myeloid lineage
| Autor: | Jui-Chung Chiang, 江瑞中 |
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| Rok vydání: | 2016 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 104 Hematopoiesis is the process to form blood components and replenish the blood system, including myeloid cell differentiation which is one of the most crucial physiological processes. Our previous studies demonstrated that lysophosphatidic acid (LPA), through activating G-protein-coupled receptors of LPA1-6, regulates myeloid cell differentiation. However, the underlie mechanisms in vivo remain unclear. In this study, we aimed to validate the effects of LPA and its corresponding receptors, LPA2 and LPA3 on erythropoiesis/megakaryopoiesis. Analyzing LPA receptors profile of mice myeloid cells, we observed that LPA2 and LPA3 express at different stages of progenitors. Mice injected with LPA2 agonist, GRI977143, showed decrease in both erythroid and megakaryocytic lineages. GRI treatment was further found to suppress common myeloid progenitor (CMP) and megakaryocyte erythrocyte progenitor (MEP) populations, suggesting that LPA2 dominantly inhibits myeloid differentiation at the early stage of myelopoiesis. In contrast, treatment with LPA3 agonist, 1-oleoyl-2-O-methyl-rac-glycerophosphothionate (OMPT), seems to induce erythropoiesis at the expense of megakaryopoiesis, as evidenced by increase in erythroid populations and RBC numbers but decreased megakaryocyte populations. Moreover, the mRNA expression levels of myeloid specific transcription factors were altered in response to GRI and OMPT, suggesting that LPA2 and LPA3 exert opposing effects on myeloid transcriptional regulations. Finally, OMPT injection successfully restored PHZ-induced acute haemolytic anaemia. Taken together, this study demonstrated for the first time that LPA2 and LPA3 differently regulate hematopoiesis in vivo, and provide a potential therapeutic strategy for the treatment of anemia. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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