Ifnα Mediated Remodeling of the Bone Marrow Stem Cell Vascular Niche

In the bone marrow (BM), endothelial cells (ECs) are a major component of the hematopoietic stem cell (HSC) vascular niche and are a first line of defense against inflammatory stress and infection. The primary response of an organism to infection involves the synthesis of immune-modulatory cytokines, including interferon alpha (IFNα). In the BM, IFNα induces rapid cell cycle entry of HSCs in vivo. However, the effect of acute IFNα treatment on BM ECs has not been described. Here, we demonstrate that IFNα leads to rapid stimulation of BM ECs in vivo, resulting in increased BM vascularity and vascular leakage. We find that stimulation of BM ECs involves the expression of key inflammatory and EC-stimulatory markers, including ESAM, VE-Cadherin and Laminin. Using the anti-VEGF antibody, Avastin, we could confirm that IFNα-mediated activation of BM ECs is dependent in part on VEGF signaling in BM hematopoietic cell types, including HSCs. Thus, this implies a role for HSCs in remodeling of the BM niche in vivo followinginflammatory stress. Taken together, these data increase our current understanding of the relationship between HSCs and the BM niche under inflammatory stress. In addition, we have clarified the response of BM niche ECs to acute IFNα treatment in vivo. IFNα treatment has been associated with anti-angiogenic effects in patients and therefore our described acute response of the BM vasculature may additionally inform future regimes of combination therapy.