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Mechanisms and implications of epithelial cell plasticity in the bladder

Nature Reviews Urology volume 23, pages 70–88 (2026)Cite this article

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Abstract

Cellular plasticity, the ability of cells to reprogramme and alter their fate, has a pivotal role in maintaining homeostasis and facilitating tissue regeneration after injury. The bladder urothelium, a dynamic transitional epithelial layer, displays a highly plastic phenotype that enables its remarkable regenerative capacity in response to wounding. During both development and repair, urothelial cells exhibit considerable plasticity through processes such as dedifferentiation, transdifferentiation and epithelial-to-mesenchymal transition. Urothelial plasticity is not only crucial for healthy tissue repair but is also involved in pathological conditions, including cancer. In bladder tumorigenesis, urothelial cells exploit plasticity to acquire new phenotypic and functional characteristics, transitioning between distinct cellular states. This plasticity contributes to tumour heterogeneity, subtype switching, progression, metastasis and resistance to therapies. These dynamic cellular transitions are regulated by intrinsic and extrinsic factors, including transcriptional and epigenetic mechanisms, as well as microenvironmental influences. Targeting urothelial plasticity could offer novel therapeutic strategies for bladder-related diseases.

Key points

  • Epithelial cell plasticity contributes to bladder repair, but leads to metaplastic changes, fibrosis and malignancy risk under pathological conditions such as inflammation or mechanical irritation.

  • Cellular plasticity drives bladder cancer heterogeneity, progression and therapy resistance through dynamic lineage transitions, epithelial-to-mesenchymal transition and stem-like traits, underscoring its pivotal role in disease evolution and treatment challenges.

  • Epithelial plasticity in bladder repair and cancer is regulated by transcription factors, signalling pathways, epigenetic modifications and microenvironmental cues, driving cell transitions and phenotypic adaptations.

  • Targeting epithelial cell plasticity offers promising avenues for bladder disease, regenerative medicine and cancer treatment.

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Fig. 1: The hierarchical structure of bladder urothelium.
Fig. 2: Manifestations of urothelial plasticity during bladder development and repair.
Fig. 3: Lineage plasticity triggers the heterogeneity and aggressive nature of bladder cancer.
Fig. 4: Molecular mechanisms regulating bladder urothelial plasticity.
Fig. 5: Detection of and therapeutic strategies for lineage plasticity.

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Acknowledgements

This work was supported by the nationally funded Postdoctoral Researcher Program (GZC20231821), China Postdoctoral Science Foundation (2024M752256) and the National Natural Science Foundation of China (reference number 82403074).

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  1. These authors contributed equally: Kan Wu, Xu Liu, Jiapeng Zhang.

Authors and Affiliations

  1. Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China

    Kan Wu, Jiapeng Zhang, Xianding Wang & Xiang Li

  2. Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, Chengdu, China

    Xu Liu

  3. Department of Urology, Institute of Urology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Chong Chen

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Contributions

K.W. and X. Liu researched data for the article. K.W., J.Z., X. Liu and C.C. contributed substantially to discussion of the content. K.W., X. Liu and J.Z. wrote the article. X.W., K.W., C.C. and X. Li reviewed and/or edited the manuscript before submission.

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Wu, K., Liu, X., Zhang, J. et al. Mechanisms and implications of epithelial cell plasticity in the bladder. Nat Rev Urol 23, 70–88 (2026). https://doi.org/10.1038/s41585-025-01066-y

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