Myeloid cell fate decisions in ischemic neovascularization: Regulation of monocyte and macrophage subsets by Notch signaling and functional significance for arteriogenesis.

• Applicant: Professor Dr. Florian P. Limbourg
• Subject Area: Cardiology, Angiology
• Term: from 2013 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233508151

Ischemia causes an inflammatory response intended to initate vascular repair and regeneration, but often leads to chronic inflammation and demise. Heterogeneity of monocytes and macrophages is a hallmark of the innate immune system and a paradigm for context-dependent myeloid plasticity. However, lineage-relationships and molecular pathways regulating monocyte and macrophage heterogeneity are not well understood. Hematopoietic cell fate decisions and ischemic tissue regeneration are regulated by Notch signaling, which is specified by various Notch ligands activating different Notch receptors. Our own results show that Notch signaling influences monocyte subset composition but also functional macrophage polarization in ischemia, which regulates a balance between ischemic tissue regeneration and chronic inflammation. We propose to address how Notch signaling regulates monocyte and macrophage cell fate and function. We will investigate the lineage relationships between monocyte and macrophage subsets and characterize the functional role of Notch signaling. Specifically, we address the hypothesis that monocyte subsets are influenced by different Notch receptors regulating lineage conversion and/or functional maturation. We will also study how the vascular endothelium regulates monocyte subsets and function through Notch ligands, and whether the spleen provides a niche for Notch signaling, thus contributing to monocyte education. We will further investigate the lineage relationships between monocyte subsets and ischemic macrophages, comprehensively characterize the trancriptional programm activated during monocyte-to-macrophage differentiation and study the regulation of macrophage phenotype and function by specific Notch receptors. These experiments are expected to identify mechanisms regulating myeloid plasticity and lineage relationships, deepening our understanding of the regulation of inflammation. This might also identify specific molecular pathways and cell populations involved in ischemic tissue regeneration, which might enable new therapeutic modalities.

• DFG Programme: Research Grants