3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a Selective Antagonist of Sphingosine-1-phospahte Receptor Subtype 1, Enhances AMD3100-stimulated Mobilization of Hematopoietic Stem Progenitor Cells in Animals.
Sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, regulates various physiological functions. We observed that the S1P receptor subtype 1 (S1P1), a high affinity G-protein coupled receptor of S1P, is the major S1P receptor expressed in the Kit+/Sca-1+/Lin-(KSL) hematopoietic stem progenitor cells (HSPCs, KSL-HSPCs). In this study, we investigate function of S1P1receptors in the regulation of HSPC mobilization in animals. Treatment with SEW2871, a specific agonist of S1P1, had no effect on KSL-HSPC mobilization. In addition, mice pretreated with SEW2871 followed by AMD3100, a well-known activator of KSL-HSPC mobilization by antagonizing the stromal-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling axis, did not enhance the AMD3100-induced KSL-HSPC mobilization. In contrast, pretreatment of (R)-3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a selective antagonist of S1P1, significantly augments AMD3100-induced KSL-HSPC mobilization into peripheral blood. The inactive enantiomer W140 was incapable of enhancing the AMD3100-induced KSL-HSPC mobilization. Moreover, treatment with selective antagonists for S1P2and S1P3had no effects on AMD3100-mediated KSL-HSPC mobilization. Collectively, our data suggest that S1P/S1P1signaling regulates the SDF-1/CXCR4-mediated retention of KSL-HSPCs in bone marrow microenvironment.
Bioactive Lipid Research Program, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202.
Jingjing
J
Liu
Bioactive Lipid Research Program, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202.
Jiawei
J
Zhao
Bioactive Lipid Research Program, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202.
Jen-Fu
JF
Lee
Bioactive Lipid Research Program, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202.
Allison
A
Gartung
Bioactive Lipid Research Program, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202.
Hiba
H
Jawadi
Bioactive Lipid Research Program, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202.
Wenliang
W
Zhang
Department of Physiology and Biophysics, University of Louisville School of Medicine, HSC A-1115, 500 South Preston Street, Louisville, KY 40202.
David
D
Lominadze
Bioactive Lipid Research Program, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Cardiovascular Research Institute, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202 ; Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 540 E. Canfield Avenue, Scott Hall room 9215, Detroit, Michigan 48202.
Menq-Jer
MJ
Lee
CXCR4; SDF-1; W146; hematopoietic stem cells; sphingosine-1-phosphate; sphingosine-1-phosphate receptor