Abstract
Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that acts through G protein-coupled receptors (LPA1-6). Although several biological roles of LPA4 are becoming apparent, its role in hematopoiesis has remained unknown. Here, we show a novel regulatory role for LPA4 in hematopoiesis. Lpar4 mRNA was predominantly expressed in mouse bone marrow (BM) PDGFRα+ stromal cells, known as the components of the hematopoietic stem/progenitor cell (HSPC) niche. Compared with wild-type mice, LPA4-deficient mice had reduced HSPC numbers in the BM and spleen and were hypersusceptible to myelosuppression, most likely due to impairments in HSPC recovery and stem cell factor production in the BM. Analysis of reciprocal BM chimeras (LPA4-deficient BM into wild-type recipients and vice versa) indicated that stromal cells likely account for these phenotypes. Consistently, LPA4-deficient BM stromal cells showed downregulated mRNA expression of stem cell factor and tenascin-c in vitro. Taken together, these results suggest a critical and novel role for the LPA/LPA4 axis in regulating BM stromal cells.
Highlights
Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that acts through G protein-coupled receptors (LPA1-6)
Lin+ mature hematopoietic cells, Lin−Sca-1+c-Kit+ (LSK) hematopoietic stem/progenitor cell (HSPC), CD34+ LSK hematopoietic progenitor cells (HPCs) and CD34− LSK hematopoietic stem cells (HSCs) were sorted from the bone marrow (BM) cells harvested by flushing tibias and femurs (Fig. 1A)
We found that LPA4-deficient mice showed hypersusceptibility to myelosuppressive stresses, likely due to impaired stress recovery of the HSPC number in the BM
Summary
Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that acts through G protein-coupled receptors (LPA1-6). LPA4-deficient BM stromal cells showed downregulated mRNA expression of stem cell factor and tenascin-c in vitro. Taken together, these results suggest a critical and novel role for the LPA/LPA4 axis in regulating BM stromal cells. LPA4-deficient mice have increased trabecular bone density compared to wild-type (WT) mice, suggesting that LPA4 has an inhibitory effect on the osteogenic differentiation of mesenchymal stem cells (MSCs)[19]. LPA4 is presumed to play pivotal roles in various cellular processes of mesenchymal cells in multiple tissues. This has not yet been thoroughly investigated
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