Biology subjects

McCartney, E. E.

Publications and source records attributed to McCartney, E. E..

3 recordsLinked to original sources

bioRxiv2026

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.

immunology↗

bioRxiv2025

Bigh3 is essential for pulmonary fibrosis

Transforming growth factor beta (TGF-{beta})-induced gene-human, clone 3 (BIGH3) has been implicated as a biomarker of lung fibrosis. However, it is unknown if BIGH3 plays a functional role in fibrosis pathogenesis. To address this question, we used in silico, in vitro and in vivo approaches. We found that BIGH3/Bigh3 is upregulated in human lung fibrosis and mouse models of pulmonary fibrosis. We next generated a novel Bigh3 knockout (Bigh3-/-) mouse and found that while these animals exhibited lung architecture and immune cellularity that is broadly equivalent to wild-type mice, they were protected from lung fibrosis in response to bleomycin administration. In silico modeling suggested that BIGH3 can bind to integrin alpha v (ITGAV). In vitro co-culture systems revealed that activated human lung fibroblasts can elicit BIGH3 expression from human monocyte-derived macrophages. Last, macrophages elicited collagen expression from lung fibroblasts in a manner that is Bigh3-dependent. Collectively, these data suggest that Bigh3 is a product of fibroblast-macrophage interactions that is essential for the pathogenesis of lung fibrosis, possibly via interactions with ITGAV.

immunology↗

bioRxiv2024

Dermatopontin-expressing fibroblasts mediate an essential skin macrophage niche

Fibroblasts are present in all tissues and are crucial for maintaining tissue homeostasis. We previously identified fibroblasts marked by Dermatopontin (Dpt) but their role in supporting macrophage homeostasis remains unclear. Here, we generated novel mesenchymal lineage-restricted genetic tools to target Dpt expressing fibroblasts and elucidate their role in supporting skin macrophages. Transcriptional profiling, flow cytometry, and in situ hybridization uncovered two broad populations of F4/80-expressing skin macrophages, denoted by high expression of CD206 and CD64 (CD206hiCD64+), or CD11c. Targeted depletion of Dpt+ fibroblasts resulted in a profound loss of both macrophage populations. Conditional deletion of colony-stimulating factor-1 (Csf1) in Dpt+ fibroblasts revealed that CD206hiCD64+, and not CD11c+, macrophages are acutely dependent on fibroblast-derived Csf1, consistent with their higher expression of the Csf1 receptor. Following Csf1 deletion in Dpt+ fibroblasts, loss of CD206hiCD64+ macrophages were observed across the dermis, dermal white adipose tissue (dWAT), and adventitia, accompanied by a modest upregulation of fibroblast-related and extracellular matrix (ECM) genes and structural changes to the skin. Alterations to the skin network upon loss of fibroblast-derived Csf1 and CD206hiCD64+ macrophages led to a significant delay in wound healing. We also demonstrate the CSF1-CSF1R signaling pathway is functionally relevant in human systemic sclerosis, or scleroderma, as elevated levels of CSF1 produced by fibroblasts and an increased abundance of macrophages both correlate with disease severity. Our findings demonstrate the role of Dpt+ fibroblasts in regulating a Csf1-dependent macrophage niche in skin and orchestrating responses in injury and disease.

immunology↗