Haj Narmeen, Tiwari Ashish, Berihu Maria, Kher Nedaa, Nsraldeen Siraj, Holdengreber Maya, Karni-Ashkenazi Shiri, Zhou Bin, Saar Galit, Stuckey Daniel J, Vandoorne Katrien
Faculty of Biomedical Engineering (N.H., A.T., M.B., N.K., S.N., S.K.-A., K.V.), Technion-Israel Institute of Technology, Haifa.
Biomedical Core Facility, Rappaport Faculty of Medicine (M.H., G.S.), Technion-Israel Institute of Technology, Haifa.
Arterioscler Thromb Vasc Biol. 2025 Jul;45(7):1192-1206. doi: 10.1161/ATVBAHA.124.322358. Epub 2025 Jun 5.
Diabetes is characterized by chronic hyperglycemia that leads to systemic vascular complications. Hyperglycemia impairs endothelial function and promotes vascular inflammation, resulting in leukocytosis, altered hematopoiesis, and cardiovascular complications. Bone marrow endothelial cells play a pivotal role in regulating myeloid progenitor cells and leukocyte trafficking. However, the effects of diabetes on the structure and function of bone marrow vasculature remain poorly understood. To address this, we used a multiscale imaging approach integrating intravital microscopy, dynamic contrast-enhanced magnetic resonance imaging, and multispectral optoacoustic tomography to investigate diabetes-induced vascular changes in the bone marrow.
Diabetes was induced in C57BL/6J female mice using streptozotocin. Flow cytometry and histology characterized bone marrow myeloid progenitors, blood leukocytes, and bone marrow endothelial cell populations, as well as hypoxia. Intravital microscopy was used to visualize vascular density, permeability, and sprouting angiogenesis in the calvarial marrow. Dynamic contrast-enhanced magnetic resonance imaging quantified vascular density and permeability in the femoral marrow, while multispectral optoacoustic tomography assessed hemoglobin oxygenation in the calvarial marrow.
Hyperglycemia significantly increased myelopoiesis, leading to elevated leukocytosis driving diabetic inflammation. Flow cytometry and histology revealed increased bone marrow endothelial cell numbers (=0.0006), while intravital microscopy showed elevated vascular permeability (=0.0095) and sprouting angiogenesis (=0.0095). Dynamic contrast-enhanced magnetic resonance imaging confirmed greater vascular density (=0.019) and leakiness (=0.0062), and multispectral optoacoustic tomography detected reduced hemoglobin oxygenation and increased hypoxia in the diabetic marrow (=0.0065), reflecting a hypoxic niche favorable to hematopoietic stem and progenitor cells. This likely drives angiogenesis and contributes to inflammatory hematopoiesis in diabetes.
This study demonstrates that diabetes induces profound vascular remodeling and hypoxia in the bone marrow, reshaping the hematopoietic niche and driving myelopoiesis and leukocytosis. By validating dynamic contrast-enhanced magnetic resonance imaging and multispectral optoacoustic tomography as noninvasive translational tools, coupled with intravital microscopy, we provide a comprehensive framework for exploring novel therapies targeting bone marrow vasculature to mitigate inflammation-driven outcomes in diabetes.
糖尿病的特征是慢性高血糖，可导致全身血管并发症。高血糖会损害内皮功能并促进血管炎症，导致白细胞增多、造血改变和心血管并发症。骨髓内皮细胞在调节髓系祖细胞和白细胞运输中起关键作用。然而，糖尿病对骨髓脉管系统结构和功能的影响仍知之甚少。为解决这一问题，我们采用了一种多尺度成像方法，将活体显微镜检查、动态对比增强磁共振成像和多光谱光声断层扫描相结合，以研究糖尿病诱导的骨髓血管变化。
使用链脲佐菌素诱导C57BL/6J雌性小鼠患糖尿病。通过流式细胞术和组织学对骨髓髓系祖细胞、血液白细胞、骨髓内皮细胞群体以及缺氧情况进行表征。利用活体显微镜观察颅骨骨髓中的血管密度、通透性和发芽血管生成。动态对比增强磁共振成像量化股骨骨髓中的血管密度和通透性，而多光谱光声断层扫描评估颅骨骨髓中的血红蛋白氧合情况。
高血糖显著增加了骨髓生成，导致白细胞增多加剧，引发糖尿病炎症。流式细胞术和组织学显示骨髓内皮细胞数量增加（P = 0.0006），而活体显微镜检查显示血管通透性升高（P = 0.0095）和发芽血管生成增加（P = 0.0095）。动态对比增强磁共振成像证实血管密度更高（P = 0.019）和渗漏增加（P = 0.0062），多光谱光声断层扫描检测到糖尿病骨髓中的血红蛋白氧合降低和缺氧增加（P = 0.0065），这反映了有利于造血干细胞和祖细胞的低氧微环境。这可能驱动血管生成并导致糖尿病中的炎症性造血。
本研究表明，糖尿病会在骨髓中引发深刻的血管重塑和缺氧，重塑造血微环境并驱动骨髓生成和白细胞增多。通过验证动态对比增强磁共振成像和多光谱光声断层扫描作为非侵入性转化工具，并结合活体显微镜检查，我们提供了一个全面的框架，用于探索针对骨髓脉管系统的新型疗法，以减轻糖尿病中炎症驱动的后果。
