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Abstract

A subset of monocytes, termed patrolling monocytes (pMos), have key effector functions in maintaining vascular integrity at steady state. We and others have shown that pMos play important roles in diminishing disease burden in atherosclerosis, tumour metastases, and Alzheimer’s disease. However, little is known about the development of these cells and their roles in these diseases due to limited numbers of these cells in circulation. Harnessing the Notch2-Delta Like Ligand 1 (DLL1) pathway, we propagated pMos in vitro that were phenotypically similar to their in vivo blood counterparts. Characterization of the in vitro grown pMos by flow cytometry and RNA sequencing revealed similar expression patterns of key pMo surface proteins and genes compared to their blood counterparts. In vitro grown pMos were also successfully transferred into recipient mice and found in organs, such as in the lungs and liver. We developed a system with the potential to grow large quantities of bona fide pMos from murine bone marrow in vitro for further studies into pMo development and therapeutic potential in diseases. Our lab previously identified Lyn tyrosine kinase as a negative regulator of pMos and demonstrated that Lyn deficient mice possess a significant expansion of pMos in circulation. We therefore used Lyn-/- mice to assess the potential protective roles of pMos in certain diseases. We found that Lyn deficient mice were protected from high fat diet-induced obesity and fatty liver disease and had expanded adipose- and liver-associated pMo populations. Utilizing mass cytometry (CyTOF), we also dissected macrophage and monocyte populations in the white adipose tissue in wt and Lyn-/- mice on normal chow or high fat diet. We also observed that Lyn deficiency in mice resulted in a decreased lung metastatic tumour burden and improved antibody-directed therapy in a model of tumour metastases. Finally, in a model of Alzheimer’s disease, we found that Lyn deficiency results in decreased brain plaque burdens. Overall, these studies demonstrated the importance of furthering our understanding of pMo development and regulation, as well as their role in blood and tissues in diseases.