Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells
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Mateusz Adamiak1,2, Lakshman Chelvarajan3, Kevin R. Lynch4, Webster L. Santos5, Ahmed Abdel-Latif3 and Mariusz Z. Ratajczak1,2
1Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
2Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
3Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
4Department of Pharmacology University of Virginia, Charlottesville, VA, USA
5Department of Chemistry, Center for Drug Discovery, Virginia Tech, Blacksburg, VA, USA
Mariusz Z. Ratajczak, email: [email protected]
Keywords: S1P, Sphk1, Sphk2, stem cell mobilization
Received: July 02, 2017 Accepted: July 14, 2017 Published: July 24, 2017
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.
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