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B10: Developmental endothelial locus-1: A regulator of hematopoietic cell adhesion and function

Project leader: Prof. Dr. T. Chavakis

 Integrin-dependent adhesive interactions between leukocytes and the endothelium contribute to inflammatory processes. In addition, similar adhesive events between haematopoietic stem cells (HSC) and bone marrow stromal cells, including endothelial cells, play a major role for the mobilisation of HSC into peripheral blood and for the homing of HSC to the bone marrow, both processes being relevant for bone marrow transplantation. The beta2-integrin LFA-1, exclusively expressed on cells of haematopoietic origin, is a major adhesion receptor in this context. We recently identified developmental endothelial locus-1 (Del-1 or Edil3), secreted by endothelial cells, as an endogenous inhibitor of LFA-1-dependent leukocyte adhesion to endothelial cells in vitro and leukocyte recruitment in vivo as well as of interleukin-17 (IL-17)-dependent inflammation in the context of aging-associated inflammatory bone loss. Since LFA-1 can regulate adhesive functions of HSC and IL-17 can affect HSC mobilization, we hypothesize that Del-1 is a major regulator of HSC mobilization. Our preliminary findings show that Del-1 is expressed in the bone marrow stroma and antagonizes granulocyte-colony stimulation factor (GCSF)-mediated mobilization of HSC from the bone marrow into the periphery. Thus, here we will study the expression and function of Del-1, as an LFA-1- and IL-17-antagonist in the course of GCSF-induced HSC mobilization and will assess the role of Del-1 in HSC engraftment to the bone marrow in the course of bone marrow transplantation. The characterization of this function of Del-1 will not only substantially broaden our understanding of the processes of HSC mobilization and engraftment but will also allow for therapeutically targeting of Del-1 to improve HSC mobilization in the course of bone marrow transplantation in the future.

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Funding program:

DFG