Identifying the niche of perivascular immune cells – PeriNiche

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The first task of PeriNiche concisted in creating different mouse models indicated in the proposal (ie various Cre mouse models bearing conditional alleles of Csf1 and Scf). These mice have been generated and are now being investigated. Preliminary experiments suggest that mesenchymal cells (probably fibroblasts) produce CSF1 in the skin and that deletion of Csf1 in mesenchymal cells drastically alters the number of dermal macrophages (BAJENOFF lab).
For mast cells, haploinsufficiency of Scf causes a reduction of dermal mast cells. More specific targeting of Scf depletion in keratinocytes, endothelial cells, vascular smoth muscle cells (VSMC) and fibroblasts are in progress. RNAseq data suggest a role of VSMC-derived Scf, whereas immunofluorescence analysis of Scf-reporter animals suggests an involvement of a fibroblast subset in providing Scf to dermal mast cells (LAMMERMANN Lab). Although these results are preliminary, it appears that the working hypotheses of PeriNiche were valid. The BAJENOFF and LAMMERMANN labs are currently confirming these preliminary observations with larger batch of mice. Then, and as indicated in the table displayed in « B », we will determine whether the various mutant mice suffer from the deficiency of macrophages and mast cells in the skin.

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Immune cells distribute throughout all tissues to protect our body from pathogens. It has long been acknowledged that macrophages (Mf) and mast cells (MCs) localize to the outer surfaces of cutaneous blood vessels and regulate their functions. However, the molecular identity of this crosstalk is largely unknown. In particular, we are missing a detailed understanding about how different vessel types and vascular components shape the specific ‘’niche’’ that regulates the identity and function of perivascular immune cells in the skin. By using in situ imaging in combination with mouse genetics, we will investigate (a) the role of specific blood vessel components (endothelial cells, pericytes, vascular smooth muscle cells, nerves) in regulating the homeostasis and defining the phenotype of perivascular Mf and MCs, and (b) the signals and molecules that control the perivascular localization of these cells. Our studies will provide novel insight into both, the local regulation of perivascular immune cells, as well as the physiological functions they exert in the skin, findings that likely can be extrapolated to other peripheral tissues.