By John Byon, MD, PhD, and Michael Linenberger, MD

2009-07-01

Drs. Byon and Linenberger indicated no relevant conflicts of interest.

Goessling W, North TE, Loewer S et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell. 2009;136:1136-47.

Hoggatt J, Singh P, Sampath J et al. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood. 2009. [Epub ahead of print]

Hematopoietic stem cell (HSC) transplantation is used to treat a variety of malignant and benign hematologic disorders. Many efforts over the years have been directed at enhancing HSCs to make this process safer, more efficient, and more widely available. Previous observations indicate that Wnt signaling and prostaglandin (PG) E₂ activation pathways regulate HSC survival and self-renewal. Two recent studies shed new light on these mechanisms and their potential utility as modifiable targets for therapeutic applications.

Goessling et al., working in Leonard Zon’s laboratory at Children’s Hospital in Boston, used mutant zebrafish expressing fluorescent reporter genes to show that PGE₂ activates Wnt signaling, increases the generation of long-term repopulating HSCs and endothelial cells in embryos, and enhances recovery of HSCs in irradiated adult fish. PGE₂ expansion of HSCs is associated with decreased apoptosis and increased proliferation. Indomethacin, a cyclooxygenase inhibitor, abrogates these activities. Studies of zebrafish expressing inducible negative regulators of Wnt signaling revealed that PGE₂ and Wnt pathways interact at the level of β-catenin via cAMP/PKA. These molecular interactions and functional consequences are conserved across species, as PGE₂ increases Wnt-mediated repopulation of murine HSCs in bone marrow transplantation assays and marrow recovery after irradiation. PGE₂/Wnt activation also enhances liver regrowth after partial hepatectomy, suggesting that this pathway is a master regulator of organ regeneration.

In a complementary study, Hoggatt et al., in Louis Pelus’ laboratory in Indianapolis, reported that PGE₂ enhances HSC homing, survival, and proliferation. Competitive repopulation transplants into congenic, hybrid mice revealed that in vitro exposure of whole bone marrow or lineage-negative progenitors to PGE₂ for only two hours increases the repopulating frequencies of long-term HSCs by 3- to 4-fold. Surprisingly, a single pulse-exposure to PGE₂ causes sustained effects as evidenced by increased chimerism in secondary transplant recipients and, interestingly, preferential myeloid reconstitution. PGE₂ up-regulates CXCR4 expression on murine and human umbilical cord blood HSCs and enhances their chemotaxis to an SDF-1 gradient in vitro. Mice transplanted with HSCs after brief PGE₂ treatment show a 2-fold greater homing efficiency and this effect is blocked by co-incubation with AMD3100, a CXCR4 antagonist. PGE₂ also appears to inhibit HSC apoptosis by up-regulating survivin expression, and it stimulates proliferation by increasing cell cycling.

These studies are significant for delineating the functional and molecular effects of PGE₂ on HSCs, the intersection of the PGE₂ and Wnt pathways at the level of β-catenin stabilization, and the possibility that PGE₂ agonists could be exploited for applications in stem cell transplantation and organ regeneration. Several unresolved issues and caveats exist, however. Wnt signaling in the hematopoietic microenvironment involves complex interactions and equilibrium between ligands, antagonists, niche cells, and HSCs, and excessive Wnt perturbation can lead to HSC depletion.^1-3 Moreover, Wnt family proteins are operational in many tumors. Thus, PGE₂ stimulation might promote neoplasia under some conditions. Therefore, therapeutic approaches to Wnt pathway manipulation, even with highly selective agents, will need to be carefully evaluated in the context of their effects on the target cell population and on tissue interactions within the physiological microenvironment.

1. Scheller M, Huelsken J, Rosenbauer F et al. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006;7:1037-47. 

2. Fleming HE, Janzen V, Lo Celso C et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008;2:274-83.

3. Malhotra S, Kincade PW. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell. 2009;4:27-36.

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