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 Blood, 28 May 2009, Vol. 113, No. 22, pp. 5444-5455.
Prepublished online as a Blood First Edition Paper on March 26, 2009; DOI 10.1182/blood-2009-01-201335.

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Submitted January 26, 2009
Accepted March 18, 2009

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

Jonathan Hoggatt, Pratibha Singh, Janardhan Sampath, and Louis M. Pelus*

Department of Micobiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States

* Corresponding author; email: lpelus{at}iupui.edu.

Adult hematopoietic stem cells (HSC) 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 HSC express PGE2 receptors, and that short-term ex vivo exposure of HSC to prostaglandin E2 (PGE2) enhances their homing, survival and proliferation, resulting in increased long-term repopulating cell (LTRC) and competitive repopulating unit (CRU) frequency. HSC 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 and 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.


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