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

Jonathan Hoggatt, Khalid 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 Farag, Magdalena Czader, Ginger L. Milne, Richard M. Breyer, Carlos H. Serezani, David T. Scadden, Theresa Guise, Edward SrourLouis Pelus

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

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Hematopoietic Stem Cells
Prostaglandins
Stem Cells
Prostaglandins E
Receptors, Prostaglandin E, EP2 Subtype
Anti-Inflammatory Agents
Stem Cell Niche
Osteopontin
Non-Steroidal Anti-Inflammatory Agents
Knockout Mice
Cell Communication
Pharmaceutical Preparations
Primates
Cell Movement
Blood Cells
Healthy Volunteers
Homeostasis
Transplantation
Bone Marrow
Transplants

ASJC Scopus subject areas

  • General

Cite this

Hoggatt, J., Mohammad, K., Singh, P., Hoggatt, A. F., Chitteti, B. R., Speth, J. M., ... Pelus, L. (2013). Differential stem-and progenitor-cell trafficking by prostaglandin e 2. Nature, 495(7441), 365-369. https://doi.org/10.1038/nature11929

Differential stem-and progenitor-cell trafficking by prostaglandin e 2. / Hoggatt, Jonathan; Mohammad, Khalid; 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; Czader, Magdalena; Milne, Ginger L.; Breyer, Richard M.; Serezani, Carlos H.; Scadden, David T.; Guise, Theresa; Srour, Edward; Pelus, Louis.

In: Nature, Vol. 495, No. 7441, 21.03.2013, p. 365-369.

Research output: Contribution to journalArticle

Hoggatt, J, Mohammad, K, Singh, P, Hoggatt, AF, Chitteti, BR, Speth, JM, Hu, P, Poteat, BA, Stilger, KN, Ferraro, F, Silberstein, L, Wong, FK, Farag, S, Czader, M, Milne, GL, Breyer, RM, Serezani, CH, Scadden, DT, Guise, T, Srour, E & Pelus, L 2013, 'Differential stem-and progenitor-cell trafficking by prostaglandin e 2', Nature, vol. 495, no. 7441, pp. 365-369. https://doi.org/10.1038/nature11929
Hoggatt J, Mohammad K, Singh P, Hoggatt AF, Chitteti BR, Speth JM et al. Differential stem-and progenitor-cell trafficking by prostaglandin e 2. Nature. 2013 Mar 21;495(7441):365-369. https://doi.org/10.1038/nature11929
Hoggatt, Jonathan ; Mohammad, Khalid ; 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 ; Czader, Magdalena ; Milne, Ginger L. ; Breyer, Richard M. ; Serezani, Carlos H. ; Scadden, David T. ; Guise, Theresa ; Srour, Edward ; Pelus, Louis. / Differential stem-and progenitor-cell trafficking by prostaglandin e 2. In: Nature. 2013 ; Vol. 495, No. 7441. pp. 365-369.
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