Indiana University-Purdue University Indianapolis (IUPUI) / 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. We have demonstrated that mouse and human HSC express prostaglandin E2 (PGE2) receptors, and that short-term ex vivo exposure of HSC to PGE2 enhances their homing, survival and proliferation, resulting in increased long-term repopulating cell 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 multiple serial transplantations, with full multi-lineage reconstitution. PGE2 increases HSC CXCR4 mRNA and surface expression and enhances their migration to SDF-1α 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. While PGE2 pulse of HSC promotes HSC self-renewal, blockade of PGE2 biosynthesis with non-steroidal anti-inflammatory drugs (NSAIDs) results in expansion of bone marrow hematopoietic progenitor cells (HPC). We co-administered NSAIDs along with the mobilizing agent granulocyte-colony stimulating factor (G-CSF) and evaluations of limiting dilution transplants, assays monitoring neutrophil and platelet recoveries, and secondary transplantations, clearly indicate that NSAIDs facilitate mobilization of a hematopoietic graft with superior functional activity compared to the graft mobilized by G-CSF alone. Enhanced mobilization has also been confirmed in baboons mobilized with G-CSF and a NSAID. Increases in mobilization are the result of a reduction of signaling through the PGE2 receptor EP4, which results in marrow expansion and reduction in the osteoblastic HSC niche. We also identify a new role for cannabinoids, an eicosanoid with opposing functions to PGE2, in hematopoietic mobilization. Additionally, we demonstrate increased survival in lethally irradiated mice treated with PGE2, NSAIDs, or the hypoxia mimetic cobalt chloride. Our results define novel mechanisms of action whereby eicosanoids regulate HSC and HPC function, and characterize novel translational strategies for hematopoietic therapies.

Mit der vorliegenden Habilitationsschrift habe ich den Versuch unternommen, die beiden Themenkomplexe meiner bisherigen wissenschaftlichen Tätigkeit als Beispiele für die Rolle von Modellen in der klinischen Forschung zu verwenden. Den Ansto§ dazu gaben Diskrepanzen, die mir in der Auseinandersetzung mit eigenen Ergebnissen und Beobachtungen im Umfeld dieser Themenkomplexe aufgefallen sind: der Rolle kontaminierender Tumorzellen in der Hochdosistherapie maligner Tumoren einerseits und dem Enzym Dipeptidylpeptidase IV (DPP IV) andererseits. Die beobachteten Diskrepanzen sind Ausdruck konkurrierender pathophysiologischer oder therapeutischer Modelle, und die Präferenz eines bestimmten Modells scheint nicht rein rational erklärbar. Welche Faktoren tragen jedoch zur Entscheidung für oder gegen ein bestimmtes Modell bei? Ich möchte den Umgang mit wissenschaftlichen Modellen anhand der genannten Themenkomplexe aus meiner Sicht erörtern. Anschlie§end soll ein Entwurf skizziert werden, in dem die der Entscheidung für oder gegen ein therapeutisches Modell zugrundeliegende Motivationslage besser verständlich wird und die Intentionalität klinischer Forschung auf den Patienten hin berücksichtigt. / In the thesis presented here, I have taken the challenge to use the topics of my scientific work to discuss the role that models appear to exert in clinical science. This decision arose from discrepancies that became evident in the comparative assessment of my own studies in relation with the surrounding scientific context: the role of tumor cells contaminating peripheral blood or progenitor cell harvests as part of a high-dose chemotherapy regimen on the one hand, and the enzyme dipeptidyl peptidase IV (DPP IV) on the other. The observed discrepancies appear to result from competing pathophysiological or therapeutic models, and the preference or rejection of one model apparently cannot be explained solely by rational factors. I will discuss the application of models in the context of the topics which my scientific work has been focusing on, and I will develop a draft proposal which will render the individual motivational status underlying the decision in favor of or against a distinct model easier to understand, with attention to the intentionality of clinical research towards the patient.

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