# Multimodal analyses of early, untreated systemic sclerosis skin identify a proinflammatory vascular niche of macrophage-fibroblast signaling

## TL;DR

This study identifies early immune and fibroblast interactions in skin of systemic sclerosis patients, revealing a proinflammatory vascular niche linked to disease progression.

## Contribution

The study reveals a novel proinflammatory vascular niche in early systemic sclerosis involving macrophage-fibroblast signaling via PDGF, TGF-β, and PI3K-AKT-mTOR pathways.

## Key findings

- Activated myeloid cells and fibroblasts in vascular niches express CXCL12, APOE, and C7 in early systemic sclerosis skin.
- SSc macrophages secrete PDGF and TGF-β to activate fibroblasts, with spatial colocalization around vasculature.
- PI3K/AKT/mTOR signaling is enriched in immunomodulatory niches, driven by profibrotic growth factor networks.

## Abstract

Uncovering the early interactions and spatial distribution of dermal fibroblasts and immune cells in treatment-naive patients with diffuse cutaneous systemic sclerosis (SSc) is critical to understanding the earliest events of skin fibrosis. We generated an integrated multiomic dataset of early-stage, treatment-naive diffuse cutaneous SSc skin. Skin biopsies were analyzed by single-nuclei multiome sequencing (snRNA-Seq and snATAC-Seq) and two spatial transcriptomic methods to comprehensively determine molecular changes. We identified an immunomodulatory niche within the papillary, hypodermis, and vascular regions enriched for activated myeloid cells and fibroblasts characterized by expression of genes such as CXCL12, APOE, and C7. Pathway analyses showed significant enrichment of PI3K/AKT/mTOR signaling pathway expression in these cellular niches, driven by profibrotic growth factor signaling networks. Macrophage subclustering showed SSc-specific macrophage activation of IL-6/JAK/STAT signaling and enrichment of oxidative phosphorylation pathways. Ligand-receptor analysis revealed that SSc macrophages secrete PDGF and TGF-β to activate SSc-dominant fibroblast subclusters. Spatial transcriptomic analyses showed monocyte-derived MRC1+ macrophages express PDGF near PDGFRhiTHY1hi fibroblasts. Multiomic data integration and spatial transcriptomic neighborhood analysis revealed the colocalization of fibroblasts, macrophages, and T cells around the vasculature. These data suggest that interactions between activated immune cells and immunomodulatory fibroblasts around vascular niches are an early event in scleroderma pathogenesis.

Multimodal omic approaches of early, untreated systemic sclerosis skin identified a proinflammatory vascular niche characterized by macrophage-fibroblast interactions involving PDGF, TGF-β and PI3K-AKT-mTOR signaling