Identifying the stromal KIT ligand (SCF) sources that maintain mast cell homeostasis in tissues
MARTZLOFF P. 1, BAMBACH S. 1, AIZARANI N. 1,2, GLASER K. 1, MIHLAN M. 1, LÄMMERMANN T. 1
1 Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany; 2 Friedrich Miescher Institute, Basel, Switzerland
Background and Objectives
Mast cells (MCs) are tissue-resident immune cells, best known for their roles in allergies and anaphylaxis. For their differentiation, survival and tissue homeostasis, MCs critically depend on stem cell factor (SCF, KIT ligand) and signaling through the receptor c-KIT. We recently showed that the periarteriolar space is an anatomical site of high SCF expression within the mouse dermis (Kaltenbach*, Martzloff*, Bambach* et al., Nat Immunol. 2023). A subset of MCs positions to these regions in an integrin-dependent manner and acquire a mature MC phenotype. However, we are still missing a clear picture which stromal cells are functionally relevant SCF sources to maintain MC homeostasis in tissues.
By using scRNAseq analysis of perivascular stromal cells and confocal imaging of SCF-reporter mice, we identified several SCF-expressing stromal cell types in the periarteriolar space: endothelial cells, vascular smooth muscle cells (VSMCs) and fibroblasts. We established mouse models to conditionally and selectively deplete SCF in these stromal cells and analyzed its impact on MC skin homeostasis.
When we depleted SCF in endothelial cells in Tek-Cre Scffl/fl mice, MC numbers and homeostasis in adult mice were not affected. In contrast to published work, K14-Cre driven SCF depletion in keratinocytes did not show gross alterations of MC homeostasis in our hands. However, Pdgfra-Cre Scffl/fl mice, which deplete SCF in fibroblasts and other stromal cell types, show strong phenotypes, including impaired MC development in peripheral tissues. Ongoing work attempts to establish more refined mouse models for fibroblast-specific SCF depletion and address the role of VSMCs in providing SCF to endogenous MCs.
Our study aims at mapping the functional distribution of stromal cell-expressed SCF in mouse tissues. We expect to gain novel insight into the mechanisms of how growth factors mediate phenotypes of tissue-resident immune cells, exemplified for MCs.