# Differential Contributions of Fibroblast Subpopulations to Intercellular Communication in Eosinophilic Esophagitis

## TL;DR

This study identifies two types of fibroblasts in eosinophilic esophagitis and shows how they contribute to cell communication and fibrosis.

## Contribution

The study reveals fibroblast subpopulations in eosinophilic esophagitis and their distinct roles in intercellular communication and fibrosis.

## Key findings

- Two fibroblast subpopulations (F_A and F_B) were identified in eosinophilic esophagitis.
- F_B fibroblasts contribute more to cell communication and ECM-receptor signaling in active disease.
- ACTA2+ fibroblasts show distinct gene expression patterns compared to ACTA2− fibroblasts.

## Abstract

Eosinophilic esophagitis is a chronic disease that can be complicated by fibrosis and strictures in the esophagus. Fibroblasts are a cell type that are considered important mediators of this process. The aim of this study was to better understand how fibroblasts can cause strictures by using publicly available single-cell RNA sequencing data to identify the different types of fibroblasts in patients with eosinophilic esophagitis. We identified at least two types of fibroblasts in eosinophilic esophagitis. Our analysis shows that fibroblasts are important contributors to the communication that occurs between cells in the human esophagus and that each of the fibroblast types has a unique way of interacting with other cell types (e.g., with epithelial cells or immune cells). This work can be used to provide additional insights into how strictures form in eosinophilic esophagitis.

Fibroblast heterogeneity remains undefined in eosinophilic esophagitis (EoE), an allergic inflammatory disorder complicated by fibrosis. We utilized publicly available single-cell RNA sequencing data (GSE201153) of EoE esophageal biopsies to identify fibroblast sub-populations, related transcriptomes, disease status-specific pathways and cell–cell interactions. IL13-treated fibroblast cultures were used to model active disease. At least 2 fibroblast populations were identified, F_A and F_B. Several genes including ACTA2 were more enriched in F_A. F_B percentage was greater than F_A and epithelial–mesenchymal transition upregulated in F_B vs. F_A in active and remission EoE. Epithelial–mesenchymal transition was also upregulated in F_B in active vs. remission EoE and TNF-α signaling via NFKB was downregulated in F_A. IL-13 treatment upregulated ECM-related genes more profoundly in ACTA2− fibroblasts than ACTA2+ myofibroblasts. After proliferating epithelial cells, F_B and F_A contributed most to cell–cell communication networks. ECM–Receptor interaction strength was stronger than secreted or cell–cell contact signaling in active vs. remission EoE and significant ligand–receptor pairs were driven mostly by F_B. This unbiased analysis identifies at least 2 fibroblast sub-populations in EoE in vivo, distinguished in part by ACTA2. Fibroblasts play a critical role in cell–cell interactions in EoE, most profoundly via ECM–receptor signaling via the F_B sub-group.