Visualizing Vascular Bone Marrow Niche Alterations in Diabetes - The 72nd Annual Conference of the Israel Heart Society in association with the Israel Society of Cardiothoracic Surgery

Narmeen Haj ¹ Ashish Tiwari ¹ Maria Berihu ¹ Nedaa Kher ¹ Siraj Narselden ¹ Maya Holdengreber ² Shiri Karni-Ashkenazi ¹ Bin Zhou ³ Galit Saar ² Daniel J. Stuckey ⁴ Katrien Vandoorne ¹

¹Biomedical Engineering, Technion-Israel Institute of Technology, Israel
²Biomedical Core Facility, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Israel
³New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China
⁴Centre for Advanced Biomedical Imaging, University College London, United Kingdom

Introduction: Diabetes, characterized by chronic hyperglycemia, leads to systemic vascular complications. It impairs endothelial function and promotes vascular inflammation, resulting in leukocytosis, altered hematopoiesis, accelerated atherosclerosis, and cardiovascular complications. Bone marrow endothelial cells play a pivotal role in regulating myeloid progenitor cells and leukocyte trafficking contributing to increased cardiovascular risk. However, the effects of diabetes on the structure and function of bone marrow vasculature remain poorly understood. To address this, we employed a multiscale imaging approach integrating intravital microscopy, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and multispectral optoacoustic tomography (MSOT).

Materials and Methods: Diabetes was induced in C57BL/6J 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. DCE-MRI quantified vascular density and permeability in the femoral marrow, while MSOT assessed hemoglobin oxygenation in the calvarial marrow.

Results and discussion: Hyperglycemia led to increased myelopoiesis, evidenced elevated leukocytosis driving diabetic inflammation. Flow cytometry and histology showed heightened endothelial cell numbers, while intravital microscopy revealed increased vascular density, permeability and sprouting angiogenesis in diabetic bone marrow. DCE-MRI confirmed heightened vascular density and leakiness, while MSOT demonstrated reduced hemoglobin oxygenation and hypoxia in the diabetic marrow, indicating a hypoxic environment in which HSPCs thrive. This hypoxia likely triggers angiogenesis, contributing to enhanced vascular remodeling, elevated leukocytosis and inflammatory hematopoiesis in diabetes.

Conclusion: 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 DCE-MRI and MSOT as non-invasive translational tools, coupled with intravital microscopy, we provide a comprehensive framework for exploring novel therapeutic strategies that target bone marrow vasculature to mitigate inflammation-driven outcomes in diabetes.