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B13: Iron regulation of the hematopoietic stem and progenitor cell niche

Project leader: Prof. Dr. med. L. Hofbauer / Prof. Dr. med. U. Platzbecker

 Iron is essential for life. In addition to erythropoiesis, iron modulates several key functions of the bone marrow microenvironment. The role of reduced or elevated body iron content on the cross-talks between MSC and HSPC within the stem cell niche and the underlying mechanisms are poorly defined. In previous studies, we identified Wnt5a as an MSC-derived cytokine that is up-regulated by TNF-α and ligands of Toll-like receptors both in mice and men. In turn, Wnt5a controls the production of various chemokines relevant for HSPC function. Moreover, our studies indicate that iron inhibits MSC differentiation and suggest a critical involvement of Wnt5a. By contrast, our data show that transferrin receptor 2 (TfR2) knock-out mice, which are systemically iron-overloaded, display erythrocytosis and an abnormally reduced frequency of HSPC-derived osteoclasts, resulting in more bone tissue. Thus, we hypothesize that iron is a critical determinant of HSPC fate as well as the MSC-mediated niche function. We will clarify the mechanisms of how iron controls the interaction of HSPC with the niche and define the contribution of the Wnt signaling pathway in this process by: (I) studying the concurrent effects of iron overload on HSPC and MSC function in TfR2-deficient mice, (II) analyzing the specificity of these effects by administration of iron chelators and use of mice that lack only the TfR2 β-isoform, but have no systemic iron overload, and (III) studying the effects of iron on the Wnt5a signaling pathway in HSPC and MSC.

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Funding program:

DFG