title: Differential stem- and progenitor-cell trafficking by prostaglandin E2.
abstract: 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. 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 E2 (PGE2) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 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 niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically.
authors.affiliation: Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hoggatt
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Pratibha
authors.initials: P
authors.lastname: Singh
authors.forename: Amber F
authors.initials: AF
authors.lastname: Hoggatt
authors.forename: Brahmananda R
authors.initials: BR
authors.lastname: Chitteti
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Speth
authors.forename: Peirong
authors.initials: P
authors.lastname: Hu
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Poteat
authors.forename: Kayla N
authors.initials: KN
authors.lastname: Stilger
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferraro
authors.forename: Lev
authors.initials: L
authors.lastname: Silberstein
authors.forename: Frankie K
authors.initials: FK
authors.lastname: Wong
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Farag
authors.forename: Magdalena
authors.initials: M
authors.lastname: Czader
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Serezani
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.forename: Louis M
authors.initials: LM
authors.lastname: Pelus
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001596:Benzylamines; D002452:Cell Count; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D000080027:Cyclams; D015232:Dinoprostone / Q000378:metabolism*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D000077239:Meloxicam; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics; D010215:Papio; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013843:Thiazines; D013844:Thiazoles; D053495:Osteopontin; D015232:Dinoprostone; C088327:plerixafor; D000077239:Meloxicam