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Activation of lysophosphatidic acid receptors regulate differentiation of hematopoietic stem cells in myeloid lineage
Author(s) -
Lin Kuan-Hung,
Chiang Jui-Chung,
Yao Chao-Ling,
Lee Hsinyu
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00713
Subject(s) - lysophosphatidic acid , microbiology and biotechnology , biology , haematopoiesis , gata1 , stem cell , receptor , erythropoiesis , cellular differentiation , hematopoietic stem cell , gata2 , biochemistry , medicine , gene , anemia
Lysophosphatidic acid (LPA) is a membrane‐derived lysophospholipid that exists in plasma and platelet. It exerts its functions through activating various LPA receptors (LPARs), which belong to the family of G‐protein coupled receptors (GPCRs). Activation of LPARs has been implicated for important roles during stem cell differentiation. However, how LPA affects human hematopoietic stem cell (HSC) differentiation and underlying lineages remains elusive. In our previous studies, we have demonstrated that activation of LPA receptor 3 (LPA 3 ) promotes erythropoiesis in human HSC and zebrafish. In the present study, pharmacological approach was adopted to further elucidate the functions of LPA receptors during red blood cell (RBC) differentiation. Treatment of LPA 2 agonist GRI977143 suppressed erythropoiesis, whereas activation of LPA 3 by 2S‐OMPT promoted RBC differentiation both in vitro and in vivo . Furthermore, our results demonstrated a negative role of LPA 3 during platelet differentiation both in vitro and in vivo . Moreover, the expression pattern of LPA receptors correlated to the hematopoietic transcriptional factors GATA1 and GATA2 in different stages of myeloid progenitors. In addition, manipulation of these GATA factors affected the expression level of LPA 2 and LPA 3 . By luciferase assays, we demonstrated that the promoter region of LPAR2 and LPAR3 were regulated by these GATA factors. Mutation of identified GATA‐Binding‐Sites (GBS) in the region abrogate the luciferase activities, suggested that LPA 2 and LPA 3 are regulated by GATA factors. In addition, chromatin immunoprecipitation assays confirmed the directly interaction between GATA factors and promoter region of LPARs. Taken together, our results suggested that the expression level of LPA 2 and LPA 3 , which may be determined by GATA factors, is a regulatory switch for the lineage commitment in myeloid progenitors. The pharmacological activation of LPA receptor subtypes represents a novel strategyfor regulating erythropoiesis.LPA receptors are expressed at different stages during myeloid differentiation. GATA switch, which is an important molecular switch in hematopoiesis, cause the difference of expressional pattern of LPA receptor in different lineage.