Regulation of macrophage maturation in ischemia: Topography and composition of the ischemic vascular niche and regulation by Notch signaling.

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Ischemia causes an inflammatory response that is intended to restore perfusion and promote healing but often aggravates damage. Macrophages are essential for growth of functional arteries in response to ischemia yet show diverse functions ranging from destructive to trophic or reparative actions. How macrophage differentiation and function is regulated during ischemia remains largely unknown. In a mouse model of hind limb ischemia we have recently shown that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and ischemic tissue recovery. Macrophage maturation is controlled by Notch ligand Dll1 expressed in vascular endothelial cells and requires macrophage canonical Notch signaling via Rbpj, which simultaneously suppresses an inflammatory macrophage fate. Furthermore, the effects of Notch activation are sufficient to generate mature macrophages from monocytes ex vivo that display a stable anti-inflammatory phenotype, even when stimulated with pro-inflammatory stimuli. We here propose to study the topography and composition of the ischemic niche and the molecular events regulating ischemic macrophage differentiation by Notch signaling. We will identify the vascular domain controlling macrophage maturation and will specifically identify the Notch receptors mediating macrophage maturation in ischemia. We will further define the growth factor context essential for ischemic macrophage maturation. We will employ genetic reporter studies and conditional deletion strategies in mouse models of hind limb ischemia as well as in vitro studies with macrophage cultures established under defined conditions to address these questions. Using these findings we will try, in a translational study, to generate human macrophages ex vivo with therapeutic potential.