Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation

Adult hematopoietic stem cells (HSCs) are routinely used to reconstitute hematopoiesis after myeloablation; however,transplantation efficacy and multilineage reconstitution can be limited by inadequate HSC number, or poor homing,engraftment, or self-renewal. Here we report that mouse and human HSCs express prostaglandin E-2 (PGE(2)) receptors, and that short-term ex vivo exposure of HSCs to PGE(2) enhances their homing, survival, and proliferation, resulting inincreased long-term repopulating cell (LTRC) and competitive repopulating unit (CRU) frequency. HSCs pulsed with PGE(2) are more competitive, as determined by head-to-head comparison in a competitive transplantation model. Enhanced HSC frequency and competitive advantage is stable and maintained upon serial transplantation, with full multilineage reconstitution. PGE(2) increases HSC CXCR4 mRNA and surface expression, enhances their migration to SDF-1 in vitro and homing to bone marrow in vivo, and stimulates HSC entry into and progression through cell cycle. In addition, PGE(2) enhances HSC survival, associated with an increase in Survivin mRNA and protein expression and reduction in intracellular active caspase-3. Our results define novel mechanisms of action whereby PGE(2) enhances HSC function and supports a strategy to use PGE(2) to facilitate hematopoietic transplantation. (Blood. 2009;113: 5444-5455)