The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells.
The novel immunosuppressant FTY720 activates sphingosine 1-phosphate receptors (S1PRs) that affect responsiveness of lymphocytes to chemokines such as stromal cell-derived factor 1 (SDF-1), resulting in increased lymphocyte homing to secondary lymphoid organs. Since SDF-1 and its receptor CXCR4 are also involved in bone marrow (BM) homing of hematopoietic stem and progenitor cells (HPCs), we analyzed expression of S1PRs and the influence of FTY720 on SDF-1/CXCR4-mediated effects in human HPCs. By reverse transcriptase-polymerase chain reaction (RT-PCR), S1PRs were expressed in mobilized CD34+ HPCs, particularly in primitive CD34+/CD38- cells. Incubation of HPCs with FTY720 resulted in prolonged SDF-1-induced calcium mobilization and actin polymerization, and substantially increased SDF-1-dependent in vitro transendothelial migration, without affecting VLA-4, VLA-5, and CXCR4 expression. In nonobese diabetic-severe combined immunodeficient (NOD/SCID) mice, the number of CD34+/CD38- cells that homed to the BM after 18 hours was significantly raised by pretreatment of animals and cells with FTY720, tending to result in improved engraftment. In addition, in vitro growth of HPCs (week-5 cobblestone area-forming cells [CAFCs]) was 2.4-fold increased. We conclude that activation of S1PRs by FTY720 increases CXCR4 function in HPCs both in vitro and in vivo, supporting homing and proliferation of HPCs. In the hematopoietic microenvironment, S1PRs are involved in migration and maintenance of HPCs by modulating the effects of SDF-1.
Department of Medicine II, University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany.
Takafumi
T
Kimura
Andreas M
AM
Boehmler
Gabriele
G
Seitz
Selim
S
Kuçi
Tina
T
Wiesner
Volker
V
Brinkmann
Lothar
L
Kanz
Robert
R
Möhle
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D018925:Chemokines / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D000068876:Fingolimod Hydrochloride; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D039041:Integrin alpha4beta1 / Q000502:physiology; D039081:Integrin alpha5beta1 / Q000502:physiology; D011409:Propylene Glycols / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D049312:Receptors, Lysophospholipid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives
D015703:Antigens, CD; D018952:Antigens, CD34; D018925:Chemokines; D007166:Immunosuppressive Agents; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D011409:Propylene Glycols; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine