Activation of Lysophosphatidic Acid Receptor 3 Inhibits Megakaryopoiesis in Human Hematopoietic Stem Cells and Zebrafish
Journal
Stem Cells and Development
Journal Volume
27
Journal Issue
3
Pages
4071
Date Issued
2018
Author(s)
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. ? Copyright 2018, Mary Ann Liebert, Inc.
SDGs
Other Subjects
beta3 integrin; fibrinogen receptor; lysophosphatidic acid; lysophosphatidic acid receptor; lysophosphatidic acid receptor 2; lysophosphatidic acid receptor 3; short hairpin RNA; stem cell factor; thrombopoietin; transcription activator like effector nuclease; unclassified drug; lysophosphatidic acid receptor; zebrafish protein; animal experiment; animal model; Article; cell differentiation; controlled study; gene knockout; hematopoietic stem cell; human; human cell; in vitro study; in vivo study; K-562 cell line; megakaryocyte; megakaryopoiesis; mRNA expression level; nonhuman; priority journal; protein expression; real time polymerase chain reaction; thrombocyte; thrombocytopoiesis; transgenic zebrafish; animal; antagonists and inhibitors; genetics; hematopoietic stem cell; metabolism; thrombocytopoiesis; zebra fish; Animals; Hematopoietic Stem Cells; Humans; Megakaryocytes; Receptors, Lysophosphatidic Acid; Thrombopoiesis; Zebrafish; Zebrafish Proteins
Publisher
Mary Ann Liebert Inc.
Type
journal article