Pharmacological activation of lysophosphatidic acid receptors regulates erythropoiesis.

Kuan-Hung Lin,Chang-Jen Huang,Shi-Hung Lin,Chao-Ling Yao,Wei-Min Chen,Ya-Hsuan Ho,Chiung-Nien Chen,Chi-Ling Chiang,Jenher Lu,Meng-Wei Li,Jui-Chung Chiang,Gabor Tigyi,Ya-Jan Yang,Yu-Nung Lin,Hsinyu Lee

doi:10.1038/srep27050

Abstract

Lysophosphatidic acid (LPA), a growth factor-like phospholipid, regulates numerous physiological functions, including cell proliferation and differentiation. In a previous study, we have demonstrated that LPA activates erythropoiesis by activating the LPA 3 receptor subtype (LPA3) under erythropoietin (EPO) induction. In the present study, we applied a pharmacological approach to further elucidate the functions of LPA receptors during red blood cell (RBC) differentiation. In K562 human erythroleukemia cells, knockdown of LPA2 enhanced erythropoiesis, whereas knockdown of LPA3 inhibited RBC differentiation. In CD34+ human hematopoietic stem cells (hHSC) and K526 cells, the LPA3 agonist 1-oleoyl-2-methyl-sn-glycero-3-phosphothionate (2S-OMPT) promoted erythropoiesis, whereas the LPA2 agonist dodecyl monophosphate (DMP) and the nonlipid specific agonist GRI977143 (GRI) suppressed this process. In zebrafish embryos, hemoglobin expression was significantly increased by 2S-OMPT treatment but was inhibited by GRI. Furthermore, GRI treatment decreased, whereas 2S-OMPT treatment increased RBC counts and amount of hemoglobin level in adult BALB/c mice. These results indicate that LPA2 and LPA3 play opposing roles during RBC differentiation. The pharmacological activation of LPA receptor subtypes represent a novel strategies for augmenting or inhibiting erythropoiesis.

Highlights

IntroductionThe definitive wave of hematopoiesis occurs in the fetal liver to produce hematopoietic stem cells (HSCs) that support the differentiation of all blood cell lineages[13,14]
It is essential for the viability of the embryo[12]
LPA2 and LPA3 expression is differentially regulated during hemin-induced erythropoiesis in K562 cells

Summary

Introduction

The definitive wave of hematopoiesis occurs in the fetal liver to produce hematopoietic stem cells (HSCs) that support the differentiation of all blood cell lineages[13,14]. Recent studies suggest that LPA plays an important role in regulating primitive hematopoiesis through activation of LPA115. It has been shown that LPA promotes myeloid differentiation in the human bone marrow microenvironment[16]. LPA was recently shown to promote the differentiation of the myeloid/macrophage lineage from human CD34+ hematopoietic progenitors via activation of LPA2 in vitro[4,5]. Corollary evidence suggests that LPA might regulate HSC differentiation and blood cell homeostasis. We have demonstrated previously the role of LPA3 in red blood cell (RBC) differentiation[17]. Our results demonstrate that LPA2 and LPA3 exert opposing roles on RBC differentiation in vitro and in vivo. We highlighted that 2S-OMPT, a LPA3 agonist, is a potential drug candidate that enhances erythropoiesis in vivo

Methods

Results

Conclusion