Targeting blood stem cell activity and extramedullary monocytopoiesis to treat atherosclerosis

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Monocytes adhere and infiltrate the vascular bed in the early stages of atherosclerosis. Once they have entered the vascular wall they differentiate into macrophages, which are known to amplify vascular inflammation. While many pro-inflammatory features of macrophages are already known (e.g. the role of the inflammasome, diminished efferocytosis, impaired netrin-1 dependent emigration), surprisingly little is known about the supply of these cells. Particularly under inflammatory conditions, hematopoietic stem and progenitor cells are released from the bone marrow and seed the spleen, where they give rise to myeloid progenitor cells (GMP and MDP), which then give rise to pro-inflammatory monocytes. Interestingly, myocardial infarction induces the release of hematopoietic stem and progenitor cells from the bone marrow with consecutively increased extramedullary monocytopoiesis, which in turn further aggravates vascular inflammation. While the bone marrow niche has been intensively studied in the last few years, the so-called splenic hematopoietic niche remains poorly understood. However, especially splenic hematopoiesis is a hallmark for many chronic inflammatory processes and leads to the generation of monocytes. Own preliminary work indicates that particularly splenic endothelial cells are crucially involved in the regulation of extramedullary monocytopoiesis. Inhibition of an endothelial adhesion molecule (e-selectin) reduces proliferation rates of hematopoietic stem and progenitor cells in the spleen and is accompanied by profound athero-protective effects in an animal model of atherosclerosis (ApoE-/-). The next step will be to decipher the interaction between splenic endothelial cells and hematopoietic stem and progenitor cells; specifically, we will investigate whether differentiation and proliferation of myeloid progenitor cells as well as an altered release of proliferative cytokines from splenic endothelial cells may be responsible for the observed effects. Further, we will image hematopoietic stem and progenitor cells in the spleen and analyze their anatomical localization in the context of chronic inflammatory base line conditions. To this end, we will use different transgenic mouse models (e.g. endothelial specific knockout mice), transplantation model of murine spleens, and various other cellular and molecular technologies, including imaging methods, such as FMT/CT. Splenic endothelial cells will be FAC-sorted. The overall aim of this application is to shed light on the poorly characterized, splenic hematopoietic niche in order to develop a treatment strategy to combat vascular inflammation.