Pi16 ⁺ fibroblast-derived Csf1 shapes skin topography

Peptidase inhibitor 16 ( Pi16 )-expressing fibroblasts are found across tissues and species, but their functional role is unclear. As fibroblasts and macrophages have been proposed to exist in a reciprocal circuit, we hypothesized Pi16 ⁺ fibroblasts may regulate macrophage homeostasis. Flow cytometry revealed ∼80% of skin fibroblasts express Pi16 , leading us to investigate the role of these cells in maintaining a macrophage niche in this tissue. We generated an in vivo system where fibroblast-derived Colony Stimulating Factor 1 ( Csf1) was constitutively eliminated in Pi16 ⁺ fibroblasts by crossing animals with a Csf1fl/fl allele to mice in which the gene Pi16 drives an IresCre cassette. Deletion of Csf1 in Pi16 ⁺ fibroblasts resulted in significant diminishment of CD64 ⁺ and CD11c ⁺ macrophages alongside expansion of PDPN ⁺ YFP ⁺ fibroblasts. Alterations in cell population dynamics coincided with thickening of both the dermis and fascial compartments of the skin. Deletion of Csf1 in Pi16 ⁺ fibroblasts delayed early wound healing in a unsplinted mouse model. Loss of PI16 ⁺ fibroblasts was observed in individuals with limited (lSSc) and diffuse (dSSc) systemic Scleroderma compared to healthy controls. These findings suggest that loss of Csf1 in Pi16 ⁺ fibroblasts elicit changes in the population dynamics of skin macrophages and modifications to tissue architecture.