Interferon Alpha Mediated Activation of the Bone Marrow Stem Cell Vascular Niche

Endothelial cells (ECs) significantly influence the response of an organism to inflammation and infection. In the bone marrow, these cells form a major part of the bone marrow vascular niche, which regulates stem cell function and influences stem cell fate. The primary response to infection involves synthesis of immune-modulatory cytokines, such as interferon alpha (IFNα). We, and others, have shown that in contrast to the anti-proliferative effect of IFNα on hematopoietic stem cells (HSCs) in vitro, in vivo, IFNα induces cell cycle entry of quiescent HSCs (Essers et al. 2009). Given the contrasting outcome of in vitro and in vivo exposure of HSCs to IFNα, it is probable that niche cells and molecular maintenance signals from the niche are required for IFNα-induced activation of quiescent HSCs. Here, we now show that although interferon signaling itself in niche cells is not required for HSC activation, niche components do respond to IFNα stimulation. Of these, bone marrow ECs are rapidly and indirectly stimulated following IFNα treatment in vivo. The vascular system, lined by ECs, is a central primary responder following inflammatory insult with a multifaceted role, including transport of immune cells and promotion of a rapid return to homeostasis. We have found that IFNα stimulation in vivo results in an increased bone marrow vascularity, visualized by fluorescence imaging of cryo-sectioned murine femurs immunostained with the vascular basement membrane protein, laminin. IFNα-mediated activation of ECs involves the expression of key inflammatory and endothelial-stimulatory markers, including VE-cadherin and ESAM, and also an increased vascular leakiness in the bone marrow, demonstrated by the Evans blue assay. In accordance with this finding of vascular activation, we confirmed that VEGF, which is an established regulator of vascular dynamics, is rapidly up regulated in the bone marrow supernatant of treated mice. Furthermore, we can also demonstrate a key role for VEGF in our observed IFNα-mediated stimulation of ECs by abrogation of this activation using co-treatment with Avastin (bevacizumab) in vivo. We are now investigating the feedback from this activation of ECs on the hematopoietic system itself. In summary, these data indicate a rapid and indirect stimulation of the bone marrow vascular niche in an inflammatory setting. In addition, they support a previously undescribed cellular instruction from an activated hematopoietic system to a niche component.