Lysophosphatidic Acid Induces Erythropoiesis through Activating Lysophosphatidic Acid Receptor 3

Abstract

Lysophosphatidic acid (LPA), an extracellular lipid mediator, exerts multiple bioactivities through activating G protein-coupled receptors. LPA receptor 3 (LPA 3 ) is a member of the endothelial differentiation gene family, which regulates differentiation and development of the circulation system. However, the relationship among the LPA receptors (LPARs) and erythropoiesis is still not clear. In this study, we found that erythroblasts expressed both LPA 1 and LPA 3 , and erythropoietic defects were observed in zLPA 3 antisense morpholino oligonucleotide-injected zebrafish embryos. In human model, our results showed that LPA enhanced the erythropoiesis in the cord blood-derived human hematopoietic stem cells (hHSCs) with erythropoietin (EPO) addition in the plasma-free culture. When hHSCs were treated with Ki16425, an antagonist of LPA 1 and LPA 3 , erythropoietic process of hHSCs was also blocked, as detected by mRNA and protein expressions of CD71 and GlyA. In the knockdown study, we further demonstrated that specific knockdown of LPA 3 , not LPA 1 , blocked the erythropoiesis. The translocation of b-catenin into the nucleus, a downstream response of LPAR activation, was blocked by Ki16425 treatment. In addition, upregulation of erythropoiesis by LPA was also blocked by quercetin, an inhibitor of the b-catenin/ T-cell factor pathway. Furthermore, the enhancement of LPA on erythropoiesis was diminished by blocking c-Junactivated kinase/signal transducer and activator of transcription and phosphatidylinositol 3-kinase/AKT activation, the downstream signaling pathways of EPO receptor, suggested that LPA might play a synergistic role with EPO to regulate erythropoietic process. In conclusion, we first reported that LPA participates in EPO-dependent erythropoiesis through activating LPA 3 .

Pharmacological activation of lysophosphatidic acid receptors regulates erythropoiesis

“…We have demonstrated previously the role of LPA 3 in red blood cell (RBC) differentiation17. In the present study, we report the pharmacological dissection of specific roles of LPA GPCR subtypes in three different species.…”

“…Using human hematopoietic stem cells we have demonstrated previously that LPA enhances erythropoiesis by activating LPA 3 17. To examine the expression patterns of LPAR during differentiation, we applied hemin-induced erythropoiesis model system using the K562 cell line18.…”

Autotaxin/Lpar3 signaling regulates Kupffer's vesicle formation and left-right asymmetry in zebrafish

“…S2A). To investigate the role of Atx and Lpar3 in early embryogenesis, we used antisense morpholino oligonucleotides (MOs) against lpar3 (Chiang et al, 2011) and atx. Knockdown efficiency of the translational blocking MO was verified by western blotting (supplementary material Fig.…”

Short-course rapamycin treatment enables engraftment of immunogenic gene-engineered bone marrow under low-dose irradiation to permit long-term immunological tolerance

“…Competitive repopulation assays ruled out that rapamycin provided a nonimmunological engraftment-enhancing effect to transgene-encoding HSPCs. While rapamycin did not appear to act on HSPCs, agents that protect the HSPC niche from radiation-induced damage or foster hematopoiesis or myelopoiesis/erythropoiesis, such as lysophophatidic acid [33, 34], might promote post-HSPC transfer engraftment. Rapamycin or its analog everolimus has been reported as ‘tolerance-permissive’ in organ allograft [21] and other settings [35, 36], and it is possible that this underlies these observations.…”