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Ureterovesical junction: a stem cell niche for ureteral urothelial renewal and bladder urothelial injury repair

ABSTRACT: Epithelial stem cells are essential for lineage specification, tissue renewal, and regeneration. Here we show that ureterovesical junction (UVJ) of urinary tract harbors a major cluster of label-retaining urothelial cells that exhibit organoid-forming activities. During lineage-tracing, these Foxa2-expressing UVJ urothelial cells renew ureteral urothelium, but do not migrate into the bladder during homeostasis or mild bladder injury. Upon mechanical and chemical denudation of bladder urothelium, UVJ cells migrate rapidly into the bladder to replace bladder urothelium. This reepithelization also occurs during combination chemotherapies and severe bladder infection. Common to these injury repair processes is the early-phase and selective phosphorylation of TRKA and AKT which drives urothelial proliferation and differentiation. Nascent bladder urothelial cells derived from UVJ express both UVJ and bladder urothelial markers, signifying active remodeling influenced by intrinsic and extrinsic factors. Modulating the activities of UVJ cells may enhance bladder urothelial regeneration and combat challenging bladder diseases.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE337018 | GEO | 2026/07/30

REPOSITORIES: GEO

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Single cell transcriptomes of mouse bladder urothelium uncover novel cell type markers and urothelial differentiation characteristics.

Project description:Objectives: Much of the information to date in terms of subtypes and function of bladder urothelial cells were derived from anatomical location or by the expression of a small number of marker genes. To have a comprehensive map of the cellular anatomy of bladder urothelial cells, we performed single-cell RNA-sequencing to thoroughly characterize mouse bladder urothelium. Materials and methods: A total of 18,917 single cells from mouse bladder urothelium was analyzed by unbiased single-cell RNA sequencing. The expression of the novel cell marker was confirmed by immunofluorescence using urinary tract infections models. Results: Unsupervised clustering analysis identified 8 transcriptionally distinct cell subpopulations from mouse bladder urothelial cells. We discovered a novel type of bladder urothelial cells marked by Plxna4 that may be involved with host response and wound healing. We also found a group of basal-like cells labeled by ASPM that could be the progenitor cells of adult bladder urothelium. ASPM+ urothelial cells are significantly increased after injury by UPEC. In addition, specific transcription factors were found to be associated with urothelial cell differentiation. At the last, a number of interstitial cystitis/bladder pain syndrome-regulating genes were found differentially expressed among different urothelial cell subpopulations. Conclusions: Our study provides a comprehensive characterization of bladder urothelial cells, which is fundamental to understanding the biology of bladder urothelium and associated bladder disease.

2020-12-12 | GSE163029 | GEO

Single-cell profiling identifies rare normal mesenchymal-like urothelial cells associated with sarcomatoid urothelial carcinoma

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2026-07-30 | GSE330882 | GEO

Single-cell profiling identifies rare normal mesenchymal-like urothelial cells associated with sarcomatoid urothelial carcinoma [bulk RNA-seq]

2026-07-30 | GSE330902 | GEO

Kruppel-like factor 5 is Required for Urothelial Maturation

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2011-08-01 | E-GEOD-27014 | biostudies-arrayexpress

Kruppel-like factor 5 is Required for Urothelial Maturation

Project description:Kruppel-like transcription factor 5 (Klf5) is expressed during late embryogenesis in the forming murine bladder urothelium. Targeted disruption of the Klf5flox alleles by the ShhGfpCre transgene resulted in failure of the bladder urothelium to mature accompanied by hydronephrosis, hydroureter, and vesicoureteric reflux in all E18.5 fetuses. The bladder urothelium did not stratify nor did it express terminal differentiation markers characteristic of basal, intermediate, and umbrella cells including keratins 20, 14, and 5, and uroplakins. At E18.5, an ectopic alpha smooth muscle actin positive layer of cells was identified subjacent to the undifferentiated Klf5-deficient urothelium. The effects of Klf5 deficiency were unique to the urothelium since maturation of the epithelium comprising the bladder neck and urethra were unaffected by the lack of KLF5. mRNA microarray analysis of whole E14.5 control and Klf5 deficient bladders identified Ppar-gamma and Grhl3 as putative downstream intermediary transcription factors that regulate urothelial maturation. Transient transfection assays demonstrated that KLF5 regulated expression of the mGrhl3 promoter. These observations show that alterations in maturation of the bladder urothelium alone are sufficient to induce bladder dysfunction leading to prenatal hydronephrosis.

2011-08-02 | GSE27014 | GEO

Loss of LPAR6 and CAB39L Dysregulate Basal to Luminal Urothelial Differentiation Program Contributing to Bladder Carcinogenesis

Project description:In vitro and in vivo studies including single cell sequencing showed that LPAR6 and CAB39L play a major role in regulating basal to luminal urothelial differentiation. Their loss of function contributed to bladder carcinogenesis by dysregulating urothelial differentiation program and sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induced cancers, which recapitulated luminal and basal subtypes of human bladder cancer.

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Epigenetic and transcriptional alterations with Kmt2c and Kmt2d loss in urothelial cells

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2024-08-09 | GSE236370 | GEO

Transcription profiling by array of human female interstitial cystitis urothelial cells after inducing differentiation

Project description:Purpose: Evaluate gene expression profiles after inducing differentiation in cultured interstitial cystitis (IC) and control urothelial cells. Materials and Methods: Bladder biopsies were taken from IC patients and controls (women having surgery for stress incontinence). Primary cultures were grown in Keratinocyte Growth Medium with supplements. To induce differentiation, in some plates the medium was changed to DMEM-F12 with supplements. RNA was analyzed with Affymetrix chips. Three nonulcer IC patients were compared with three controls. Results: After inducing differentiation, 302 genes with a described function were altered at least 3-fold with p <0.01 in both IC and control cells. Functions of the162 upregulated genes included cell adhesion (e.g. claudins, occludin, cingulin); urothelial differentiation, retinoic acid pathway and keratinocyte differentiation (e.g. skin cornified envelope components). The 140 downregulated genes included genes associated with basal urothelium (e.g. p63, integrins ?4, ?5 and ?6, basonuclin 1 and extracellular matrix components), vimentin, metallothioneins and members of the Wnt and Notch pathways. Comparing IC vs. control cells after differentiation, only seven genes with a described function were altered at least 3-fold with p <0.01. PI3, SERPINB4, CYP2C8, EFEMP2 and SEPP1 were decreased in IC; AKR1C2 and MKNK1 were increased in IC. Conclusions: Differentiation-associated changes occurred in both IC and control cells. Comparing IC vs. control revealed very few differences. This study may have included IC patients with minimal urothelial deficiency and/or selected the cells that were most robust in culture. Also, the abnormal urothelium in IC may be due to post-translational changes and/or the bladder environment. Experiment Overall Design: Human female urothelial cell cultures, differentiated vs. non-differentiated,interstitial cystitis vs. control

2008-10-25 | E-GEOD-11839 | biostudies-arrayexpress

Effect of dietary increased Vitamin a on urothelial regeneration after Cyclophosphamide induced injury in mice

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Project description:Urothelium forms a distensible yet impermeable barrier, senses and transduces stimuli, and defends the urinary tract from mechanical, chemical and bacterial injuries. Biochemical and genetic labeling studies support the existence of one or more progenitor populations with the capacity to rapidly regenerate the urothelium following injury, but slow turnover, a low mitotic index, and inconsistent methodologies obscure progenitor identity. The progenitor properties of basal Keratin 5 urothelial cells (K5-UC) have been previously investigated, but those studies focused on embryonic or adult bladder urothelium. Urothelium undergoes desquamation and apoptosis after birth, which requires postnatal proliferation and restoration. Therefore, we mapped the fate of bladder K5-UCs across postnatal development/maturation and following administration of cyclophosphamide to measure homeostatic and reparative progenitor capacities, respectively. In vivo studies demonstrate that basal K5-UCs are age-restricted progenitors in neonates and juveniles, but not in adult mice. Neonatal K5-UCs retain a superior progenitor capacity in vitro, forming larger and more differentiated urothelial organoids than adult K5-UCs. Accordingly, K5-UC transcriptomes are temporally distinct, with enrichment of transcripts associated with cell proliferation and differentiation in neonates. Induction of urothelial proliferation is sufficient to restore adult K5-UC progenitor capacity. Our findings advance the understanding of urothelial progenitors and support a linear model of urothelial formation and regeneration, which may have significant impact on therapeutic development or tissue engineering strategies.

2024-01-03 | GSE248463 | GEO

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