ZFIN ID: ZDB-PUB-171215-5
Activation of Lysophosphatidic Acid Receptor 3 Inhibits Megakaryopoiesis in Human Hematopoietic Stem Cells and Zebrafish
Lin, K.H., Li, M.W., Chang, Y.C., Lin, Y.N., Ho, Y.H., Weng, W.C., Huang, C.J., Chang, B.E., Yao, C.L., Lee, H.
Date: 2017
Source: Stem cells and development   27(3): 216-224 (Journal)
Registered Authors: Chang, Bei-En, Huang, Chang-Jen, Lee, Hsinyu
Keywords: none
MeSH Terms:
  • Animals
  • Hematopoietic Stem Cells/metabolism*
  • Humans
  • Megakaryocytes/metabolism*
  • Receptors, Lysophosphatidic Acid/antagonists & inhibitors
  • Receptors, Lysophosphatidic Acid/genetics
  • Receptors, Lysophosphatidic Acid/metabolism*
  • Thrombopoiesis*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 29239275 Full text @ Stem Cells Dev.
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ABSTRACT
Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid that exists in the plasma and platelets. It exerts its functions through activation of various LPA receptors (LPARs), which belong to the family of G protein-coupled receptors. Activation of LPARs has important roles in stem cell differentiation. However, how LPA affects human hematopoietic stem cell (HSC) differentiation remains elusive. In our previous studies, we have suggested that LPA receptor 2 (LPA2) and LPA receptor 3 (LPA3) play opposing roles and may act as a molecular switch during megakaryocytic differentiation in K562 cells. In this study, human CD34+ HSCs and zebrafish are adopted to investigate the roles of LPA3 during megakaryopoiesis/thrombopoiesis in vitro and in vivo. Our results show that LPAR3 mRNA expression level is decreased upon induction by thrombopoietin and stem cell factor in human HSCs. Using pharmacological activators and shRNA knockdown experiments, we demonstrate that activation of LPA3 inhibits megakaryopoiesis in human HSCs. In addition, pharmacological activation of LPA3 suppressed thrombopoiesis in zebrafish. Furthermore, blockage of LPA3 translation by morpholino increased the number of CD41-GFP+ cells in Tg(CD41:eGFP) zebrafish. Moreover, the mRNA expression level of zCD41 increased significantly in LPA3-knockout zebrafish. These results clarify the negative role of LPA3 during megakaryopoiesis and provide important information for potential treatments of related diseases, such as megakaryopenia.
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