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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dc.contributor.authorAdamiak, Mateuszen
dc.contributor.authorChelvarajan, Lakshmanen
dc.contributor.authorLynch, Kevin R.en
dc.contributor.authorSantos, Webster L.en
dc.contributor.authorAbdel-Latif, Ahmeden
dc.contributor.authorRatajczak, Mariusz Z.en
dc.contributor.departmentChemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2019-09-30T13:21:38Zen
dc.date.available2019-09-30T13:21:38Zen
dc.date.issued2017-09-12en
dc.description.abstractSphingosine-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.en
dc.description.notesThis work was supported by NIH grants 2R01 DK074720-10 and R01HL112788, the Stella and Henry Endowment, and the Harmonia NCN grant UMO-2014/14/M/NZ3/00475 to MZR, the Preludium NCN grant UMO-2016/23/N/NZ4/03345 to MA, R01GM121075 to KRL and WLS and the UK COBRE Early Career Program (P20 GM103527) to AAL.en
dc.description.sponsorshipNIH [2R01 DK074720-10, R01HL112788]; Stella and Henry Endowment; Harmonia NCN grant [UMO-2014/14/M/NZ3/00475]; Preludium NCN grant [UMO-2016/23/N/NZ4/03345, R01GM121075]; UK COBRE Early Career Program [P20 GM103527]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.18632/oncotarget.19514en
dc.identifier.eissn1949-2553en
dc.identifier.issue39en
dc.identifier.pmid29029455en
dc.identifier.urihttp://hdl.handle.net/10919/94138en
dc.identifier.volume8en
dc.language.isoenen
dc.rightsCreative Commons Attribution 3.0 Unporteden
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subjectS1Pen
dc.subjectSphk1en
dc.subjectSphk2en
dc.subjectstem cell mobilizationen
dc.titleMobilization 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 cellsen
dc.title.serialOncotargeten
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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