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 Blood, 5 November 2009, Vol. 114, No. 19, pp. 4054-4063.
Prepublished online as a Blood First Edition Paper on September 2, 2009; DOI 10.1182/blood-2009-03-205823.

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HEMATOPOIESIS AND STEM CELLS

In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells

Benjamin J. Frisch13,*, Rebecca L. Porter13,*, Benjamin J. Gigliotti13, Adam J. Olm-Shipman13, Jonathan M. Weber13, Regis J. O'Keefe3, Craig T. Jordan2,4, and Laura M. Calvi13

1 Endocrine Division, 2 Department of Medicine, 3 Center for Musculoskeletal Research, and 4 Wilmot Cancer Center, University of Rochester School of Medicine, NY

Microenvironmental signals can determine hematopoietic stem cell (HSC) fate choices both directly and through stimulation of niche cells. In the bone marrow, prostaglandin E2 (PGE2) is known to affect both osteoblasts and osteoclasts, whereas in vitro it expands HSCs and affects differentiation of hematopoietic progenitors. We hypothesized that in vivo PGE2 treatment could expand HSCs through effects on both HSCs and their microenvironment. PGE2-treated mice had significantly decreased number of bone trabeculae, suggesting disruption of their microarchitecture. In addition, in vivo PGE2 increased lineage– Sca-1+ c-kit+ bone marrow cells without inhibiting their differentiation. However, detailed immunophenotyping demonstrated a PGE2-dependent increase in short-term HSCs/multipotent progenitors (ST-HSCs/MPPs) only. Bone marrow cells transplanted from PGE2 versus vehicle-treated donors had superior lymphomyeloid reconstitution, which ceased by 16 weeks, also suggesting that ST-HSCs were preferentially expanded. This was confirmed by serial transplantation studies. Thus in vivo PGE2 treatment, probably through a combination of direct and microenvironmental actions, preferentially expands ST-HSCs in the absence of marrow injury, with no negative impact on hematopoietic progenitors or long-term HSCs. These novel effects of PGE2 could be exploited clinically to increase donor ST-HSCs, which are highly proliferative and could accelerate hematopoietic recovery after stem cell transplantation.


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