Imaging the Vascular Bone Marrow Niche During Inflammatory Stress

Inflammatory stress induced by exposure to bacterial lipopolysaccharide causes hematopoietic stem cell expansion in the bone marrow niche, generating a cellular immune response. As an integral component of the hematopoietic stem cell niche, the bone marrow vasculature regulates the production and release of blood leukocytes, which protect the host against infection but also fuel inflammatory diseases. We aimed to develop imaging tools to explore vascular changes in the bone marrow niche during acute inflammation. Using the Toll-like receptor ligand lipopolysaccharide as a prototypical danger signal, we applied multiscale imaging to characterize how the bone marrow vasculature adapts when hematopoiesis boosts leukocyte supply. Endothelial Itgav expression was elevated 3 hours after lipopolysaccharide treatment. Integrin αVβ3 staining was increased and localized at the outer surfaces of the vessels in the marrow of lipopolysaccharide-treated mice. We detected integrin αVβ3+ Ki67+ endomucin+ endothelial cells, indicating that proliferating bone marrow endothelial cells stain for αVβ3 integrins concomitant with hypoxic conditions in response to prototypical inflammatory stress. Fluorescence and positron emission tomography integrin αVβ3 imaging signal increased during lipopolysaccharide-induced vascular remodeling. Vascular leakiness, quantified by albumin-based in vivo microscopy and magnetic resonance imaging, rose when hematopoietic stem and progenitor cells proliferated more vigorously and Ly6G+ neutrophils departed. Introducing a tool set to image bone marrow either with cellular resolution or noninvasively within the entire skeleton, this work sheds light on angiogenic responses that accompany emergency hematopoiesis. Understanding and monitoring bone marrow vasculature during inflammatory responses may provide a key to unlock therapeutic targets regulating systemic inflammation.