Regulation of monocyte cell fate by blood vessels through Notch signaling and significance for vascular repair

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Injury of blood vessels triggers an inflammatory response intended to eliminate the inciting agent and initiate repair and regeneration. This response involves the interaction of monocytes and blood vessels, which are in constant crosstalk with each other under physiological and pathological conditions. A subpopulation of monocytes, known as patrolling or Ly6Clo monocytes, patrol blood vessels by crawling along the vascular endothelium. Patrolling monocytes are involved in tissue repair after ischemia, but also orchestrate endothelial repair after injury. However, the origin and regulation of these monocytes is still largely unknown, and their significance for endothelial recovery after injury incompletely understood. In preliminary work we have defined the molecular and cellular context that regulates the origin of this monocyte subset. Taken together, our results show that Notch signaling regulates conversion of conventional (Ly6Chi) monocytes into Ly6Clo monocytes, thereby regulating a specific developmental step in monocyte cell fate under steady-state conditions. This process is controlled specifically by a Notch ligand expressed by a population of EC that constitute distinct vascular niches in the bone marrow and spleen. Thus, blood vessels regulate monocyte conversion, as a form of developmental cell fate regulation.We now intend to define the molecular mechanism and vascular niche constituents that govern Ly6Clo monocyte development and aim to analyze their significance in models of endothelial injury. Specifically, based on preliminary data, we hypothesize that Notch signaling interacts with the TLR signaling pathway during the development of patrolling monocytes and will test this mechanism in vitro and in vivo. We will characterize the specific vascular function of patrolling monocytes and monocyte Notch signaling in established models of endothelial repair after carotid endothelial injury. We will further characterize the vascular niche and test the specific role of the spleen for the development and function of patrolling monocytes in physiological conditions, but also the relevance of the splenic niche function in endothelial injury and repair. Finally, we will aim to develop in vitro culture system for human patrolling monocytes with the intention to use them for treatment purposes.We propose therefore to study the mechanisms defining monocyte cell fate and elucidate fundamentals of inflammation and vascular repair. The knowledge of this might be crucial for the design of efficient treatment strategies in the therapy of inflammatory diseases.