Monocyte differentiation in the ischemic bone marrow niche in limb ischemia and regulation by Notch signaling

• Applicant: Dr. Tamar Kapanadze
• Subject Area: Clinical Immunology and Allergology ; Cardiology, Angiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470129213

Limb ischemia causes an inflammatory response characterized by recruitment of “classical” Ly6Chi monocytes to ischemic tissues, where cells differentiate into monocyte-derived macrophages with reparative and pro-angiogenic functions. This process is critically controlled by Notch signaling. Ischemic inflammation is accompanied by an early response of the bone marrow (BM) niche, which enables expansion of the monocyte lineage to sustain monocyte production and egress to ischemic tissue. This involves changes in vascular and stromal compartments of the BM niche and stimulation of monocyte progenitors that give rise to Ly6Chi classical monocytes. New findings demonstrate that Ly6Chi monocytes can develop from two distinct lineages, via monocyte-dendritic cell progenitors (MDP) or common monocyte progenitors (cMoP), which might have consequences for monocyte function. However, the effects of ischemia on the vascular BM niche, monocyte progenitors and the resultant monocyte populations remain unclear. This is the focus of the grant proposal. Based on our own published work and in preliminary results presented here we propose to study the impact of ischemia on monopoiesis and resultant monocyte fate. We aim to determine, whether ischemia influences proliferation and apoptosis of monocytic progenitors and pathway choice (MDP vs CMoP) for monocyte differentiation. Second, we will employ conditional mutant mice in order to investigate role of Notch signaling in restoring integrity of the vascular BM niche and influencing monocyte lineage choice during the post-ischemic crosstalk between blood vessel endothelium and monocytes and their precursors.

• DFG Programme: Research Grants