The Role of the Hematopoietic Niche in Chronic Stress Promoted Atherosclerosis

• Applicant: Hana Seung
• Subject Area: Cardiology, Angiology ; Immunology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507657971

Cardiovascular diseases (CVD) represent the leading cause of death worldwide, despite continuous advances in public health, pharmacotherapy and interventional innovations. Beyond classical cardiovascular risk factors, e.g. hypertension, diabetes mellitus, etc., chronic stress has been recognized to contribute to the global CVD burden independently from other cardiovascular risk factors by fueling atherosclerotic inflammation. Intriguingly, in 2014 Heidt et al. described elevated sympathetic nervous system activity to decrease CXCL12 levels in the hematopoietic niche via β3 adrenergic signaling in mesenchymal stem cells (MSC), resulting in increased hematopoietic stem cell (HSC) proliferation, enhanced production and release of inflammatory leukocytes into circulation and advanced atherosclerotic plaque inflammation. This turned a spotlight on the hematopoietic niche as an underestimated key player in atherosclerotic inflammation, a complex multicellular network composed of bone marrow stromal cells and HSC progeny that precisely regulates HSC cell cycle progression and thus innate immune cell production.Comprehensive analyses of the hematopoietic niche have previously been restricted to reporter gene or surface marker-dependent cell sorting, likely underestimating its molecular heterogeneity and functional plasticity. Transcriptomic profiling by single cell RNA-sequencing (scRNA-seq) facilitated the creation of a refined hematopoietic niche taxonomy for homeostasis and disease models, e.g. acute myeloid leukemia and acute stress by 5-FU-treatment performed by Baryawno et al. and Tikhonova et al. in 2019, which revealed new pathophysiological trajectories. However, a systematic analysis of the hematopoietic niche for chronic stress has not yet been performed.This project aims to test the hypothesis that the hematopoietic niche harbors multiple regulatory pathways that moderate chronic stress to accelerate HSC cell cycle progression, inflammatory cell output and ultimately fuel inflammation in the setting of atherosclerosis, synergistically to β3 adrenergic signaling in MSC which decreases CXCL12 levels as shown by Heidt et al.. Revisiting the chronic variable stress model as previously used by Heidt et al. in the host lab paired with state-of-the-art scRNA-seq will generate a scRNA-seq library of all hematopoietic BM niche cells for chronic stress. This will allow objective analyses to identify top regulated genes or signaling pathways induced by chronic stress termed X. After validating altered X expression under chronic stress using qPCR, immunofluorescence microscopy and flow cytometry, a protagonist-cell-specific deletion model for X will be established to study the role of X in hematopoiesis and atherosclerotic inflammation. Targeting X therapeutically may hold the potential to increase resilience against chronic stress-induced atherosclerotic inflammation and thus reform treatment of CVD.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Matthias Nahrendorf