期刊
ONCOTARGET
卷 6, 期 22, 页码 18819-18828出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4710
关键词
Pathology Section; S1P; SDF-1; CXCR4; stem cell homing; hematopoietic stem cells
资金
- NIH [2R01 DK074720, R01HL112788, R56 HL124266]
- Stella and Henry Hoenig Endowmen
- University of Kentucky Clinical and Translational Science Pilot Award [UL1TR000117]
- UK COBRE Early Career Program [P20 GM103527]
The alpha-chemokine stromal-derived factor 1 (SDF-1), which binds to the CXCR4 receptor, directs migration and homing of CXCR4(+) hematopoietic stem/progenitor cells (HSPCs) to bone marrow (BM) stem cell niches. Nevertheless, it is also known that CXCR4(-/-) fetal liver-derived hematopoietic stem cells engraft into BM and that blockade of CXCR4 by its antagonist AMD3100 does not prevent engraftment of HSPCs. Because of this finding of SDF-1-CXCR4-independent BM homing, the unique role of SDF-1 in HSPC homing has recently been challenged. While SDF-1 is the only chemokine that chemoattracts HSPCs, other chemoattractants for these cells have recently been described, including the bioactive phosphosphingolipid sphingosine-1-phosphate (S1P). To address the potential role of S1P in homing of HSPCs to BM, we performed hematopoietic transplants into mice deficient in BM-expressed sphingosine kinase 1 (Sphk1(-/-)) using hematopoietic cells from normal control mice as well as cells from mice in which floxed CXCR4 (CXCR4(fl/fl)) was conditionally deleted. We observed the presence of a homing and engraftment defect in HSPCs of Sphk1(-/-) mice that was particularly profound after transplantation of CXCR4(-/-) BM cells. Thus, our results indicate that BM-microenvironment-expressed S1P plays a role in homing of HSPCs. They also support the concept that, in addition to the SDF-1-CXCR4 axis, other chemotactic axes are also involved in homing and engraftment of HSPCs.
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