Attenuated crosstalk between urothelium and fibroblasts promotes ureteral stricture development

TL;DR

This study finds that reduced communication between urothelial cells and fibroblasts contributes to the development of ureteral strictures, a type of urinary tract blockage.

Contribution

The study identifies novel molecular interactions, including ANXA1 and FPR2, linking urothelial-fibroblast crosstalk to fibrotic remodeling in ureteral strictures.

Findings

Urothelial cells in ureteral stricture tissues show reduced expression of ROS-associated genes and ANXA1.

Fibroblasts in affected tissues exhibit decreased THBS1 and FPR2 receptor expression.

Impaired urothelial-fibroblast communication is linked to fibrotic remodeling in ureteral strictures.

Abstract

Ureteral stricture (US), characterized by fibrotic remodeling of the ureteral wall, represents an obstructive urological disorder with incompletely characterized pathophysiological mechanisms. This study integrates single-cell RNA sequencing (scRNA-seq) with immunohistochemical validation in human tissues to investigate the molecular and cellular mechanisms underlying US pathogenesis.

Specimens of US (n = 7) and normal ureters (n = 8) were collected from patients prospectively. Single-cell RNA sequencing was performed to dissect the transcriptomic landscape of US, with subsequent immunohistochemical and immunofluorescence staining employed to validate key molecular and cellular findings at the protein level.

In US tissues, we identified significant downregulation of urothelial cell-specific gene signatures, accompanied by attenuated intercellular crosstalk between urothelial cells and fibroblasts. The urothelial cells exhibited reduced expression of reactive oxygen species (ROS)-associated functional clusters, with ANXA1 gene demonstrating particularly pronounced downregulation compared to control samples. Additionally, fibroblasts in US tissues displayed decreased expression of the THBS1 subtype and significant reduction in fibroblast-specific FPR2 receptor.

Our findings establish that impaired urothelial cell function and disrupted urothelial-fibroblast communication are critically associated with or contributing to fibrotic remodeling in US. Specifically, control urothelial cells secrete ANXA1 as a ligand to interact with the fibroblast-expressed FPR2 receptor, maintaining fibroblast homeostasis. Clinically, these insights provide novel theoretical foundations for US prevention and highlight potential therapeutic targets for antifibrotic intervention.

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