Differential stem-and progenitor-cell trafficking by prostaglandin e 2

Jonathan Hoggatt, Khalid S. Mohammad, Pratibha Singh, Amber F. Hoggatt, Brahmananda R. Chitteti, Jennifer M. Speth, Peirong Hu, Bradley A. Poteat, Kayla N. Stilger, Francesca Ferraro, Lev Silberstein, Frankie K. Wong, Sherif S. Farag, Magdalena Czader, Ginger L. Milne, Richard M. Breyer, Carlos H. Serezani, David T. Scadden, Theresa A. Guise, Edward F. SrourLouis M. Pelus

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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 E 2 (PGE 2) on HSC function ex vivo. 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 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. PGE 2 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.

Original languageEnglish (US)
Pages (from-to)365-369
Number of pages5
JournalNature
Volume495
Issue number7441
DOIs
StatePublished - Mar 21 2013

ASJC Scopus subject areas

  • General

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