Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by complex cellular heterogeneity and inflammatory dysfunction in the bladder. However, the molecular pathogenesis of IC/BPS remains poorly understood, and few studies have provided comprehensive analyses. To elucidate the mechanisms underlying disease pathology, we performed integrated single-cell and spatial transcriptomic analyses of human bladder tissue. Comprehensive single-cell multiomics analyses have identified disease-specific alterations across multiple cell types. T helper 17 cells were significantly expanded in Hunner lesions and activated autoimmune and pro-inflammatory signaling pathways, suggesting a critical role in disease progression. Endothelial cells (ECs) shift from homeostatic (EC2) to pro-angiogenic inflammatory phenotypes (EC3), contributing to vascular remodeling. In the monocyte-macrophage lineage, we identified macrophage 2 cells with pro-angiogenic features that engaged in vascular endothelial growth factor-mediated and tumor necrosis factor-mediated interactions that promoted pathological angiogenesis. Smooth muscle cells (SMCs) display notable phenotypic plasticity, transitioning from a contractile to a synthetic state in IC/BPS tissues. Additionally, spatial transcriptomic analysis revealed upregulation of the EDN1-EDNRA/EDNRB signaling axis, suggesting a role for SMCs in bladder hypercontractility. Fibroblasts have emerged as key mediators of nociceptive signaling, with specific subpopulations enriched in neurotrophin-related pathways (for example, NTF3-NTRK2/NTRK3 and NGF-SORT1) and showing active crosstalk with SMCs, potentially contributing to the development of chronic pain. Collectively, these findings delineate a complex stromal-immune-vascular network underlying the pathological remodeling and pain characteristics of IC/BPS. Our study identified novel cellular players and intercellular signaling pathways that may be promising targets for therapeutic interventions.
Experimental & molecular medicine. 2026 Jul 03 [Epub ahead of print]
ByulA Jee, IJun Kim, Cheol Lee, Yeon Jeong Kim, Kyunghee Park, Ji-Hee Sung, Inwoo Hwang, Jung-Sun Kim, Kyu-Sung Lee, Kwang Jin Ko, Minyong Kang
Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea., Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea., Translational Genomics Center, Samsung Medical Center, Seoul, South Korea., Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. ., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. .