Publication Date:
2013-03-15
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606692/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606692/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoggatt, Jonathan -- Mohammad, Khalid S -- Singh, Pratibha -- Hoggatt, Amber F -- Chitteti, Brahmananda R -- Speth, Jennifer M -- Hu, Peirong -- Poteat, Bradley A -- Stilger, Kayla N -- Ferraro, Francesca -- Silberstein, Lev -- Wong, Frankie K -- Farag, Sherif S -- Czader, Magdalena -- Milne, Ginger L -- Breyer, Richard M -- Serezani, Carlos H -- Scadden, David T -- Guise, Theresa A -- Srour, Edward F -- Pelus, Louis M -- CA069158/CA/NCI NIH HHS/ -- CA143057/CA/NCI NIH HHS/ -- DK07519/DK/NIDDK NIH HHS/ -- DK37097/DK/NIDDK NIH HHS/ -- HL07910/HL/NHLBI NIH HHS/ -- HL087735/HL/NHLBI NIH HHS/ -- HL096305/HL/NHLBI NIH HHS/ -- HL100402/HL/NHLBI NIH HHS/ -- P01 DK090948/DK/NIDDK NIH HHS/ -- P30 CA082709/CA/NCI NIH HHS/ -- R01 HL044851/HL/NHLBI NIH HHS/ -- R01 HL096305/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Mar 21;495(7441):365-9. doi: 10.1038/nature11929. Epub 2013 Mar 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23485965" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anti-Inflammatory Agents, Non-Steroidal/pharmacology
;
Cell Count
;
Cell Movement/physiology
;
Cells, Cultured
;
Dinoprostone/*metabolism
;
Hematopoietic Stem Cell Mobilization
;
Hematopoietic Stem Cells/*cytology/drug effects
;
Heterocyclic Compounds/pharmacology
;
Humans
;
Mice
;
Mice, Inbred C57BL
;
Mice, Knockout
;
Osteopontin/genetics
;
Papio
;
Receptors, Prostaglandin E, EP4 Subtype/genetics/metabolism
;
Stem Cells/*cytology/drug effects
;
Thiazines/pharmacology
;
Thiazoles/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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