The urothelium: a multi-faceted barrier against a harsh environment

Jafari, Nazila; Rohn, Jennifer

doi:10.1038/s41385-022-00565-0

Cited by 39 publications

(25 citation statements)

References 360 publications

(429 reference statements)

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“…The urothelium is a stratified, transitional epithelium that lines the surface of the renal pelvis, ureters, urinary bladder and proximal urethra. It serves as a barrier that prevents the diffusion of toxic substances such as acid and urea and defends against pathogens from the external environment ( Winder et al., 2014 ; Osborn and Kurzrock, 2015 ; Balsara and Li, 2017 ; Jafari and Rohn, 2022 ). The urothelium consists of three cell types: the undifferentiated basal cells, intermediate cells and terminally differentiated luminal umbrella cells ( Wu et al., 2009 ; Jaimes-Parra et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

An immunoresponsive three-dimensional urine-tolerant human urothelial model to study urinary tract infection

Jafari

Rohn

2023

Front. Cell. Infect. Microbiol.

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IntroductionMurine models of urinary tract infection (UTI) have improved our understanding of host-pathogen interactions. However, given differences between rodent and human bladders which may modulate host and bacterial response, including certain biomarkers, urothelial thickness and the concentration of urine, the development of new human-based models is important to complement mouse studies and to provide a more complete picture of UTI in patients.MethodsWe originally developed a human urothelial three-dimensional (3D) model which was urine tolerant and demonstrated several urothelial biomarkers, but it only achieved human thickness in heterogenous, multi-layered zones and did not demonstrate the comprehensive differentiation status needed to achieve barrier function. We optimised this model by altering a variety of conditions and validated it with microscopy, flow cytometry, transepithelial electrical resistance and FITC-dextran permeability assays to confirm tissue architecture, barrier integrity and response to bacterial infection.ResultsWe achieved an improved 3D urine-tolerant human urothelial model (3D-UHU), which after 18-20 days of growth, stratified uniformly to 7-8 layers comprised of the three expected, distinct human cell types. The apical surface differentiated into large, CD227+ umbrella-like cells expressing uroplakin-1A, II, III, and cytokeratin 20, all of which are important terminal differentiation markers, and a glycosaminoglycan layer. Below this layer, several layers of intermediate cells were present, with a single underlying layer of CD271+ basal cells. The apical surface also expressed E-cadherin, ZO-1, claudin-1 and -3, and the model possessed good barrier function. Infection with both Gram-negative and Gram-positive bacterial classes elicited elevated levels of pro-inflammatory cytokines and chemokines characteristic of urinary tract infection in humans and caused a decrease in barrier function.DiscussionTaken together, 3D-UHU holds promise for studying host-pathogen interactions and host urothelial immune response.

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Section: Introductionmentioning

confidence: 99%

An immunoresponsive three-dimensional urine-tolerant human urothelial model to study urinary tract infection

Jafari

Rohn

2023

Front. Cell. Infect. Microbiol.

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“…Sporadic umbrella cell exfoliation, a homeostatic urothelial mechanism ( 26 ), could be reproduced by uninfected 3D-UHU (Fig. 7C).…”

Section: Resultsmentioning

confidence: 89%

A human urothelial microtissue model reveals shared colonization and survival strategies between uropathogens and commensals

Flores,

Ling,

Loh

et al. 2023

Sci. Adv.

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Urinary tract infection is among the most common infections worldwide, typically studied in animals and cell lines with limited uropathogenic strains. Here, we assessed diverse bacterial species in a human urothelial microtissue model exhibiting full stratification, differentiation, innate epithelial responses, and urine tolerance. Several uropathogens invaded intracellularly, but also commensal Escherichia coli , suggesting that invasion is a shared survival strategy, not solely a virulence hallmark. The E. coli adhesin FimH was required for intracellular bacterial community formation, but not for invasion. Other shared lifestyles included filamentation (Gram-negatives), chaining (Gram-positives), and hijacking of exfoliating cells, while biofilm-like aggregates were formed mainly with Pseudomonas and Proteus . Urothelial cells expelled invasive bacteria in Rab-/LC3-decorated structures, while highly cytotoxic/invasive uropathogens, but not commensals, disrupted host barrier function and strongly induced exfoliation and cytokine production. Overall, this work highlights diverse species-/strain-specific infection strategies and corresponding host responses in a human urothelial microenvironment, providing insights at the microtissue, cell, and molecular level.

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“…In humans, these superficial umbrella cells are protected by a crystalline lattice comprising four uroplakins—UPK1A, UPK1B, UPKII, and UPKIII—that adorn up to 90% of the umbrella cell surface [ 70 ]. UPK1A and UPK1B are N-glycosylated and are terminated with mannose, which is the ligand for the adhesion protein, FimH, which is expressed on uropathogenic E. coli [ 71 ] and is responsible for the attachment and subsequent colonisation of the urothelium in many clinical cases of chronic UTI [ 72 ].…”

Section: The Challenge Of Recurrent Uti: Biopharmaceutical Challenges...mentioning

confidence: 99%

Effective Treatments of UTI—Is Intravesical Therapy the Future?

Morris

Rohn

Glickman³

et al. 2023

Pathogens

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Urinary tract infection (UTI) afflicts millions of patients globally each year. While the majority of UTIs are successfully treated with orally administered antibiotics, the impact of oral antibiotics on the host microbiota is under close research scrutiny and the potential for dysbiosis is a cause for concern. Optimal treatment of UTI relies upon the selection of an agent which displays appropriate pharmacokinetic-pharmacodynamic (PK-PD) properties that will deliver appropriately high concentrations in the urinary tract after oral administration. Alternatively, high local concentrations of antibiotic at the urothelial surface can be achieved by direct instillation into the urinary tract. For antibiotics with the appropriate physicochemical properties, this can be of critical importance in cases for which an intracellular urothelial bacterial reservoir is suspected. In this review, we summarise the underpinning biopharmaceutical barriers to effective treatment of UTI and provide an overview of the evidence for the deployment of the intravesical administration route for antibiotics.

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The urothelium: a multi-faceted barrier against a harsh environment

Cited by 39 publications

References 360 publications

An immunoresponsive three-dimensional urine-tolerant human urothelial model to study urinary tract infection

An immunoresponsive three-dimensional urine-tolerant human urothelial model to study urinary tract infection

A human urothelial microtissue model reveals shared colonization and survival strategies between uropathogens and commensals

Effective Treatments of UTI—Is Intravesical Therapy the Future?

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