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

• Published in: Blood Vol. 113; no. 22; pp. 5444 - 5455
• Main Authors: Hoggatt, Jonathan, Singh, Pratibha, Sampath, Janardhan, Pelus, Louis M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 28.05.2009; Americain Society of Hematology; American Society of Hematology
• Series: Hematopoiesis and Stem Cells
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Dinoprostone - pharmacology; Graft Survival - drug effects; Hematologic and hematopoietic diseases; Hematopoiesis and Stem Cells; Hematopoietic Stem Cell Mobilization - methods; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - physiology; Humans; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Receptors, CXCR4 - metabolism; Receptors, Prostaglandin E - metabolism; Transplantation Conditioning - methods; Cell proliferation; Cell survival; Hematology; Eicosanoid; Stem cell; Arachidonic acid derivatives; Hematopoietic cell; Prostaglandin E2; Homing phenomenon
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-01-201335

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 E2 (PGE2) receptors, and that short-term ex vivo exposure of HSCs to PGE2 enhances their homing, survival, and proliferation, resulting in increased long-term repopulating cell (LTRC) and competitive repopulating unit (CRU) frequency. HSCs pulsed with PGE2 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. PGE2 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, PGE2 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 PGE2 enhances HSC function and supports a strategy to use PGE2 to facilitate hematopoietic transplantation.