The vascular bone marrow niche as immunological and hematopoietic hotspot

Both hematopoietic stem cells and immune cells in the bone marrow localize in close proximity to the bone marrow vasculature, suggesting possible interactions between hematopoiesis and the immune response in the vascular bone marrow niche. In this thesis, we therefore focus on the vascular bone marrow niche as an immunological and hematopoietic hotspot. We study the role of the vascular bone marrow niche in the bone marrow entry of hematopoietic stem- and progenitor cells. We show that VE-cadherin is crucial for the regulation of bone marrow vascular permeability and bone marrow directed migration of hematopoietic progenitor cells. Next, we identify an important role for the CXCR4-CXCL12 axis for CD8⁺ T bone marrow entry and subsequent localization in vascular bone marrow niches that support their survival. In addition, we study the capacity of the vascular bone marrow niche to support hematopoiesis under inflammatory challenge, as well as its ability to translate inflammatory signals to hematopoietic output. We conclude that IFN-y negatively affects the maintenance and survival of bone marrow MSCs, and does not improve their hematopoietic support function. In addition, we suggest an important role for bone marrow dendritic cells as translators between infection and hematopoiesis, in particular in anti-fungal immunity. This thesis therefore identifies opportunities for crosstalk between hematopoiesis and immunity in the bone marrow, and invites further investigations into the organization of the vascular bone marrow niche that will be of significance for our understanding of hematopoiesis and immunological memory in both health and disease.