Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid involved in cell signaling and, if released from cells, also plays a crucial role in regulating the trafficking of lympho-hematopoietic cells, including primitive hematopoietic stem/progenitor cells (HSPCs). It has been demonstrated that S1P chemoattracts HSPCs, and its level in peripheral blood creates a gradient directing egress of these cells during mobilization. In this paper we analyzed hematopoiesis in mice deficient in sphingosine kinase 2 (Sphk2-KO mice) and studied the effect of this mutation on plasma S1P levels. We found that Sphk2-KO mice have normal hematopoiesis, and, in contrast to Sphk1-KO mice, the circulating S1P level is highly elevated in these animals and correlates with the fact that HSPCs in Sphk2-KO animals, also in contrast to Sphk1-KO animals, show enhanced mobilization. These results were recapitulated in wild type (WT) animals employing an Sphk2 inhibitor. We also administered an inhibitor of the S1P-degrading enzyme S1P lyase, known as tetrahydroxybutylimidazole (THI), to WT mice and observed that this resulted in an increase in S1P level in PB and enhanced mobilization of HSPCs. In sum, our results support a crucial role for S1P gradients in blood plasma in the mobilization process and indicate that small-molecule inhibitors of Sphk2 and Sgpl1 could be employed as mobilization-facilitating compounds. At the same time, further studies are needed to explain the unexpected effect of Sphk2 inhibition on increasing S1P levels in plasma.
Highlights
Evidence has accumulated that the bioactive lipid sphingosine-1-phosphate (S1P) is an important chemoattractant for lymphocytes [1, 2] and, together with ceramide-1-phosphate (C1P), plays a pivotal role in the trafficking of hematopoietic stem/progenitor cells (HSPCs) [2, 3]
We found that Sphk2-KO mice have normal hematopoiesis, and, in contrast to Sphk1KO mice, the circulating S1P level is highly elevated in these animals and correlates with the fact that HSPCs in Sphk2-KO animals, in contrast to sphingosine kinase — type 1 (Sphk1)-KO animals, show enhanced mobilization
The seminal observation of this report is that Sphk2null mice and mice exposed to Sphk2 and Sgpl1 inhibitors have elevated S1P levels in peripheral blood (PB) and show enhanced www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget mobilization of HSPCs
Summary
Evidence has accumulated that the bioactive lipid sphingosine-1-phosphate (S1P) is an important chemoattractant for lymphocytes [1, 2] and, together with ceramide-1-phosphate (C1P), plays a pivotal role in the trafficking of hematopoietic stem/progenitor cells (HSPCs) [2, 3]. As a bioactive lipid and a phosphorylated product of sphingosine, S1P is an important intracellular second messenger and, if released from the cells, is a ligand www.impactjournals.com/oncotarget for five different G protein-coupled S1P receptors (S1P1-5) [2, 9]. Of these receptors, S1P receptor type 1 (S1P1) and (as recently demonstrated) S1P3 [2, 10,11,12] play an important role in the trafficking of lympho/ hematopoietic cells. Mice with Sphk knockout are poor HSPC mobilizers [5] and have impaired homing of HSPCs after transplantation [16]
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