水解磷酸酯受器增效劑調控哺乳動物骨髓系統中紅血球及巨核細胞分化之研究

造血作用 (Hematopoiesis) 為一連續性的發育過程，其產生各類生物體所需之血球細胞，以維持血液系統恆定，其中骨髓系統 (Myeloid lineage) 為一重要分支，而在本實驗室過去研究指出，水解磷酸脂 (lysophosphatidic acid, LPA) 藉由活化特定受器參與調控骨髓系統中紅血球與巨核細胞的分化，因此，本篇研究透過小鼠動物模式，進一步探討LPA在哺乳動物骨髓系統中所扮演之角色。首先，透過分析LPA2和LPA3在骨髓系統中各個時期前驅細胞上的表現量，發現此兩種受器分別表現於血球分化過程中的不同時期，接著我們進一步給予此兩種受器之增效劑，GRI用以針對LPA2，而OMPT則為LPA3，並分別分析骨髓和脾臟等造血組織中各種血球前驅細胞，以及周邊血液中成熟血球細胞，實驗結果顯示，LPA2作用於上游前驅細胞，並抑制整體下游骨髓系統，使紅血球與巨核細胞的分化皆受到抑制，而LPA3則作用在較晚期的前驅細胞，促進紅血球生成，反之抑制巨核細胞的分化路徑，而這樣的分化能力則可望應用於貧血治療上，因此我們最後在苯胼 (Phenylhydrazine, PHZ) 所誘發的貧血小鼠模式中發現，OMPT對比對照組，其貧血之病徵受到減緩。本研究中所發現LPA2和LPA3兩受器在血球分化中所扮演的調控角色，可作為研究水解磷酸脂及哺乳動物骨髓系統關係之指標，並可望作為貧血治療的新興藥物。

關鍵字

造血作用；水解磷酸脂；骨髓系統；紅血球；巨核細胞；貧血

並列摘要

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.

並列關鍵字

Hematopoiesis ； Lysophosphatidic acid ； Myeloid lineage ； Erythrocyte ； Megakaryocyte ； Anemia

參考文獻

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水解磷酸酯受器增效劑調控哺乳動物骨髓系統中紅血球及巨核細胞分化之研究

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