尿路上皮
间质性膀胱炎
尿路上皮细胞
祖细胞
TLR3型
干细胞
诱导多能干细胞
再生(生物学)
化学
医学
癌症研究
泌尿科
细胞生物学
生物
膀胱
内科学
受体
泌尿系统
Toll样受体
胚胎干细胞
先天免疫系统
生物化学
基因
作者
Peng Liao,Jiawei Chen,Yuanzhuo Chen,Chi Zhang,Si‐Hong Shen,M. Liu,Yang Fan,Shufen Yang,Xiuzhen Zhang,Wei Wang,Xiaoshuai Gao,Xingpeng Di,Yue Ma,Xiao Zeng,Hong Shen,Xi Jin,Deyi Luo
摘要
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 cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.
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