Lysophosphatidic Acid Induces Erythropoiesis through Activating Lysophosphatidic Acid Receptor 3§

Authors

  • Chi-Ling Chiang,

    1. Institute of Zoology, National Taiwan University, Taipei, Taiwan, Republic of China
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  • Swey-Shen Alex Chen,

    1. Institute of Zoology, National Taiwan University, Taipei, Taiwan, Republic of China
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  • Shyh Jye Lee,

    1. Institute of Zoology, National Taiwan University, Taipei, Taiwan, Republic of China
    2. Department of Life Science, National Taiwan University, Taipei, Taiwan, Republic of China
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  • Ku-Chi Tsao,

    1. Institute of Zoology, National Taiwan University, Taipei, Taiwan, Republic of China
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  • Pei-Lun Chu,

    1. Department of Chemical Engineering and Materials Science, Yuan-Ze University, Chung-Li, Taiwan, Republic of China
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  • Cheng-Hao Wen,

    1. Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan, Republic of China
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  • Shiaw-Min Hwang,

    1. Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan, Republic of China
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  • Chao-Ling Yao,

    Corresponding author
    1. Department of Chemical Engineering and Materials Science, Yuan-Ze University, Chung-Li, Taiwan, Republic of China
    • Department of Chemical Engineering and Materials Science, Yuan Ze University, 135, Yuan-Tung road, Chung-Li city 32003, Taiwan, Republic of China
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    • Telephone: 886-3-4638800; Fax: 886-3-4559373

  • Hsinyu Lee

    Corresponding author
    1. Institute of Zoology, National Taiwan University, Taipei, Taiwan, Republic of China
    2. Department of Life Science, National Taiwan University, Taipei, Taiwan, Republic of China
    3. Center for Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China
    4. Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan, Republic of China
    5. Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
    • Department of Life Science and Institute of Zoology, National Taiwan University, 1 Roosevelt Road, Sec. 4, Taipei 106, Taiwan, Republic of China
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    • Telephone: 8862-3366-2499; Fax: 8862-2363-6837


  • Author contributions: C.-L.C.: designed the research, performed experiments, and wrote the manuscript; S.-S.A.C.: performed experiments; S.J.L.: designed and performed experiments; K.-C.T.: performed zebrafish experiments; P.-L.C. prepared human hematopoietic stem cells; C.-H.W., performed experiments; S.-M.H., provided stem cells; C.-L Y.: designed the research, prepared human hematopoietic stem cells, performed experiments, and wrote the manuscript; H.L. designed the research, and wrote the manuscript. C.-L Y. and H.L. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS September 13, 2011.

Abstract

Lysophosphatidic acid (LPA), an extracellular lipid mediator, exerts multiple bioactivities through activating G protein-coupled receptors. LPA receptor 3 (LPA3) 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 LPA1 and LPA3, and erythropoietic defects were observed in zLPA3 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 LPA1 and LPA3, 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 LPA3, not LPA1, blocked the erythropoiesis. The translocation of β-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 β-catenin/T-cell factor pathway. Furthermore, the enhancement of LPA on erythropoiesis was diminished by blocking c-Jun-activated 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 LPA3. STEM CELLS 2011;29:1763–1773

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