# New insights into interstitial cystitis/bladder pain syndrome at single‐cell resolution

## TL;DR

This paper reviews how single-cell RNA sequencing reveals cellular changes in bladder pain syndrome, including immune and urothelial alterations, and suggests possible new treatment targets.

## Contribution

The paper provides a comprehensive review of scRNA-seq findings in IC/BPS, highlighting novel cell subtypes and signaling pathways involved in the disease.

## Key findings

- IC/BPS bladders show reduced UPK3A+ umbrella cells and increased progenitor-like cells with impaired regeneration.
- Three fibroblast subtypes contribute to fibrosis and inflammation in IC/BPS.
- Immune responses in IC/BPS are Th1-biased, with exhausted CD8+ T cells and reduced regulatory T cells.

## Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory bladder disorder with unknown aetiology and limited treatment options. Single‐cell RNA‐sequencing (scRNA‐seq) has provided unprecedented insights into cellular heterogeneity in IC/BPS. This review summarizes recent scRNA‐seq findings on bladder cell populations, emphasizing urothelial, interstitial and immune cells.

A comprehensive analysis of published scRNA‐seq studies was conducted to compare bladder cell subtypes in healthy and IC/BPS‐affected bladders. Differences between IC/BPS patients and mouse models, as well as sex‐specific cellular variations, were examined.

IC/BPS bladders exhibit significant urothelial alterations, including a reduction in UPK3A + umbrella cells and an expansion of progenitor‐like cells with impaired regenerative capacity, linked to TLR3‐NR2F6 signalling. Interstitial cells include three fibroblast subtypes (PDGFRA+, RGS5+ and pro‐inflammatory IL6‐producing fibroblasts), which contribute to fibrosis and inflammation. The immune landscape is characterized by a Th1‐biased response, exhausted CD8 + T cells and reduced regulatory T cells, with HPV infection detected in most IC/BPS patients, suggesting a possible viral aetiology. Cell‐to‐cell interactions are compromised, with enhanced macrophage‐endothelial signalling via CXCL8‐ACKR1 and CXCL2/3‐ACKR1 pathways, highlighting potential therapeutic targets. Notably, sex‐based differences reveal stronger immune activation in females and increased urothelial proliferation in males, potentially explaining the higher IC/BPS prevalence in females.

scRNA‐seq has advanced our understanding of IC/BPS by identifying disease‐associated cell types, signalling pathways and intercellular interactions. Future research should integrate multi‐omics approaches and explore non‐invasive urine‐based scRNA‐seq for improved diagnosis and therapy.