From the Department of Imaging, Center for Systems Biology (K.V., D.R., H.-Y.K., G.G., G.W., L.H., F.F.H., V.F., R.N., F.H., Y.J., C.V., R.W., C.P.L., F.K.S., M.N.).
Wellman Center for Photomedicine (Y.J., C.P.L.).
Circ Res. 2018 Aug 3;123(4):415-427. doi: 10.1161/CIRCRESAHA.118.313302.
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 TLR (Toll-like receptor) ligand lipopolysaccharide as a prototypical danger signal, we applied multiparametric, multimodality and multiscale imaging to characterize how the bone marrow vasculature adapts when hematopoiesis boosts leukocyte supply. In response to lipopolysaccharide, ex vivo flow cytometry and histology showed vascular changes to the bone marrow niche. Specifically, proliferating endothelial cells gave rise to new vasculature in the bone marrow during hypoxic conditions. We studied these vascular changes with complementary intravital microscopy and positron emission tomography/magnetic resonance imaging. 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 neutrophils departed and hematopoietic stem and progenitor cells proliferated more vigorously.
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 may provide a key to unlock therapeutic targets regulating systemic inflammation.
暴露于细菌脂多糖引起的炎症应激会导致骨髓龛中的造血干细胞扩张，从而产生细胞免疫反应。作为造血干细胞龛的一个组成部分，骨髓脉管系统调节着血液白细胞的产生和释放，这些白细胞可以保护宿主免受感染，但也会引发炎症性疾病。
我们旨在开发成像工具来探索急性炎症期间骨髓龛中的血管变化。
我们使用 TLR（Toll-like receptor）配体脂多糖作为典型的危险信号，应用多参数、多模态和多尺度成像来描述造血作用增强白细胞供应时骨髓脉管系统如何适应。在脂多糖的作用下，离体流式细胞术和组织学显示骨髓龛中的血管发生变化。具体来说，在缺氧条件下，增殖的内皮细胞在骨髓中产生新的血管。我们通过互补的活体显微镜和正电子发射断层扫描/磁共振成像研究了这些血管变化。荧光和正电子发射断层扫描整合素 αVβ3 成像信号在脂多糖诱导的血管重塑过程中增加。当中性粒细胞离开，造血干细胞和祖细胞更剧烈地增殖时，通过基于白蛋白的活体显微镜和磁共振成像定量的血管通透性增加。
引入了一套在细胞分辨率下或在整个骨骼范围内进行非侵入性成像的工具集，这项工作揭示了伴随紧急造血的血管生成反应。了解和监测骨髓血管可能为解锁调节全身炎症的治疗靶点提供关键。
