Differential stem- and progenitor-cell trafficking by prostaglandin E2

Endogenous prostaglandin E 2 (PGE 2 ) is a potent regulator of haematopoietic stem cell (HSC) retention in the bone marrow; inhibition of endogenous PGE 2 signalling by non-steroidal anti-inflammatory drugs results in enhanced HSC and haematopoietic progenitor cell mobility via E-prostanoid 4 (EP4) receptor antagonism. PGE 2 regulates stem-cell retention in bone marrow The haematopoietic stem cell (HSC) microenvironment supports progenitor cells producing new circulating blood cells yet prevents the inappropriate exit of immature cells into the bloodstream. This study identifies endogenous prostaglandin E 2 (PGE 2 ) as a component in the maintenance of this delicate balance. Louis M. Pelus and colleagues show that inhibition of endogenous PGE 2 signalling by nonsteroidal anti-inflammatory drugs (NSAIDs) significantly increases the release of functional haematopoietic stem and progenitors from bone marrow into the peripheral blood, with additive effects when used in conjunction with granulocyte colony-stimulating factor. Tests in primates and human volunteers suggest a strategy that might be used therapeutically to enhance transplantation survival: administration of NSAIDs (aspirin, ibuprofen and meloxicam) enhances stem-cell mobilization, with faster haematologic recovery and enhanced long-term stem-cell repopulation of haematopoietic grafts. To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury 1 , 2 , 3 , 4 , 5 . Despite considerable advances in the specific cellular or molecular mechanisms governing HSC–niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E 2 (PGE 2 ) on HSC function ex vivo 6 , 7 . Here we show that inhibition of endogenous PGE 2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1–CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on nich