SUMMARY To maintain lifelong production of blood cells, hematopoietic stem cells (HSC) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSC (LT-HSC) reside in several, perhaps overlapping, niches that produce regulatory molecules/signals necessary for homeostasis and increased output following stress/injury 1–5. Despite significant advances in specific cellular or molecular mechanisms governing HSC/niche interactions, little is understood about regulatory function within the intact mammalian hematopoietic niche. Recently, we and others described a positive regulatory role for Prostaglandin E2 (PGE2) on HSC function ex vivo 6,7. While exploring the role of endogenous PGE2 we unexpectedly observed hematopoietic egress after nonsteroidal anti-inflammatory drug (NSAID) treatment. Surprisingly, this was independent of the SDF-1/CXCR4 axis. 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 (OPN). Hematopoietic 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 higher species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced EP4 receptor signaling. These results not only uncover unique regulatory roles for EP4 signaling in HSC retention in the niche but also define a rapidly translatable strategy to therapeutically enhance transplantation.

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We have found ferromagnetism in epitaxially grown superlattices of CaRuO(3)/CaMnO(3) that arises in one unit cell at the interface. Scanning transmission electron microscopy and electron energy loss spectroscopy indicate that the difference in magnitude of the Mn valence states between the center of the CaMnO(3) layer and the interface region is consistent with double exchange interaction among the Mn ions at the interface. Polarized neutron reflectivity and the CaMnO(3) thickness dependence of the exchange bias field together indicate that the interfacial ferromagnetism is only limited to one unit cell of CaMnO(3) at each interface. The interfacial moment alternates between the 1 μ(B)/interface Mn ion for even CaMnO(3) layers and the 0.5 μ(B)/interface Mn ion for odd CaMnO(3) layers. This modulation, combined with the exchange bias, suggests the presence of a modulating interlayer coupling between neighboring ferromagnetic interfaces via the antiferromagnetic CaMnO(3) layers.