UPK3A + umbrella cell damage mediated by TLR3–NR2F6 triggers programmed destruction of urothelium in Hunner‐type interstitial cystitis/painful bladder syndrome

作者：Liao Peng, Jiawei Chen, Yuanzhuo Chen, Chi Zhang, Si‐Hong Shen, Meng‐Zhu Liu, Yang Fan, Shi‐Qin Yang, Xiuzhen Zhang, Wei Wang, Xiaoshuai Gao, Xingpeng Di, Yu‐Cheng Ma, Xiao Zeng, Hong Shen, Xi Jin, Deyi Luo · 发表于：The Journal of Pathology · 年份：2024 · DOI：10.1002/path.6275 · 被引用次数：14 · 研究领域：Urinary Bladder and Prostate Research、Bladder and Urothelial Cancer Treatments、Urological Disorders and Treatments

Abstract Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner‐type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single‐cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A + umbrella cells and a simultaneous increase in progenitor‐like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A + umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A + umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A + umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A + umbrella ...