Work

Single-cell atlas of urethral stricture reveals fibroblast, mast cell, and macrophage heterogeneity with candidate regulators

Year: 2026

Type: article

Abstract: Background: Urethral strictures are characterized by fibrotic scar tissue formation in the urethra, leading to difficulties in urination and potential renal dysfunction. The cellular microenvironment contributes to stenosis. However, the heterogeneity of key cell types hinders our understanding of this disease. Methods: Single-cell RNA sequencing was performed on three urethral scar tissues and three normal urethral tissues. First, the main cell types and sample heterogeneity were identified. Transcription factor (TF) and enrichment analyses were used to characterize the transcriptional regulation and metabolic patterns of fibroblasts and mast cells. Finally, CellChat was used to elucidate intercellular communication networks in urethral scar tissues. Results: Of the eight cell types detected, fibroblasts, mast cells, and macrophages were major contributors to urethral scar tissue. These cells were categorized into seven (FB0-FB6), two (Mast0 and Mast1), and nine (Macro0-Macro8) subclusters, respectively, based on heterogeneity. Urethral scar tissue exhibited increased proportions of FB3 fibroblast, Mast1 mast cell, Macro1, and Macro7 Macrophages. Marker genes of these subclusters were associated with fibrosis-related biological processes, including cell adhesion and extracellular matrix organization. Additionally, screening of the dysregulation of multiple TFs and metabolic pathways revealed potential candidate TFs-ETS1 (from FB3) and SMAD3 (from Mast1)-associated with fibrosis. Furthermore, communication substantially increased between fibroblasts and other cells, and between Macro1 or Macro7 and other macrophage subclusters or fibroblasts in urethral scar tissue. Conclusions: We revealed the transcriptional characteristics of candidate cells involved in the fibrogenesis of urethral stricture, which provides insights into the pathogenesis of urethral stenosis and may facilitate the exploration of therapeutic targets.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1932042