The role of sphingosine 1-phosphate receptors in the trafficking of hematopoietic progenitor cells.

Sphingosine 1-phosphate (S1P) is an ubiquitously present extracellular lipid mediator that is released by several cell types, particularly by activated platelets. The effects of S1P are mediated by a specific family of G protein-coupled sphingosine 1-phosphate receptors (S1P1-S1P5). We demonstrate that S1P acts on hematopoietic progenitor cells as a chemotactic factor, attracting peripheral blood CD34(+) cells in vitro. Furthermore, constant activation of S1P receptors augments CXCR4-mediated signal transduction induced by stromal cell-derived factor 1 (SDF-1). These effects are most likely mediated by the S1P1 receptor consistently expressed in both primitive and committed CD34(+) hematopoietic progenitor cells (HPCs). In vivo, sustained activation of S1P1 by a receptor agonist during the homing process resulted in increased engraftment. Given the fact that activated platelets represent a major source of extracellular S1P, SDF-1-mediated stem cell homing may occur at sites of tissue injury in addition to the bone marrow. This could explain the previously observed contribution of primary hematopoietic stem cells to tissue repair in myocardial infarction and other diseases.