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Fulltext Unusual finding of endocervical-like mucinous epithelium in continuity with urothelium in endocervicosis of the urinary bladder

Cheah PL, Looi LM, Lee GE, Teoh KH, Mun KS, Nazarina AR

Diagn Pathol, 2011;6:56.
PMID: 21699710 DOI: 10.1186/1746-1596-6-56

Endocervicosis in the urinary bladder is a rare benign condition. We present a case in a 37-year-old woman with classical clinical and pathological features of endocervicosis. The unusual observation of endocervical-like mucinous epithelium in continuity with the urothelium in addition to fully developed endocervicosis prompted immunohistochemical profiling of the case using antibodies to cytokeratins (AE1/AE3, CK19, CK7, CK5/6, CK20), HBME-1, estrogen receptor (ER) and progesterone receptor (PR) to assess the relationship of the surface mucinous and endocervicosis glandular epithelia. The surface mucinous epithelium, urothelium and endocervicosis glands were immunopositive for AE1/AE3, CK7 and CK19 while CK20 was only expressed by few urothelial umbrella cells. The surface mucinous epithelium was CK5/6 and HBME-1 immunonegative but showed presence of ER and PR. This was in contrast to the urothelium's expression of CK5/6 but not ER and PR. In comparison, endocervicosis glands expressed HBME-1, unlike the surface mucinous epithelium. The endocervicosis epithelium also demonstrated the expected presence of ER and PR and CK5/6 immunonegativity. The slightly differing immunohistochemical phenotypes of the surface mucinous and morphologically similar endocervicosis glandular epithelium is interesting and requires further clarification to its actual nature. The patient has remained well and without evidence of disease 18-months following transurethral resection of the lesion.

Matched MeSH terms: Urothelium/metabolism; Urothelium/pathology*
Fulltext Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Rajandram R, Ong TA, Razack AH, MacIver B, Zeidel M, Yu W

Am J Physiol Renal Physiol, 2016 05 01;310(9):F885-94.
PMID: 26911853 DOI: 10.1152/ajprenal.00483.2015

Ketamine is a popular choice for young drug abusers. Ketamine abuse causes lower urinary tract symptoms, with the underlying pathophysiology poorly understood. Disruption of urothelial barrier function has been hypothesized to be a major mechanism for ketamine cystitis, yet the direct evidence of impaired urothelial barrier function is still lacking. To address this question, 8-wk-old female C57BL/6J mice were injected intraperitoneally with 30 mg·kg(-1)·day(-1) ketamine for 12 wk to induce ketamine cystitis. A spontaneous voiding spot assay showed that ketamine-treated mice had increased primary voiding spot numbers and smaller primary voiding spot sizes than control mice (P < 0.05), indicating a contracted bladder and bladder overactivity. Consistently, significantly increased voiding frequency was observed in ketamine-treated mice on cystometrograms. These functional experiments indicate that ketamine induces voiding dysfunction in mice. Surprisingly, urothelial permeability in ketamine-treated mice was not changed when measured using an Ussing chamber system with isotopic urea and water. Mouse urothelial structure was also not altered, and intact umbrella cell structure was observed by both transmission and scanning electron microscopy. Furthermore, immunostaining and confocal microscopy confirmed the presence of a well-defined distribution of zonula occuldens-1 in tight junctions and uroplakin in umbrella cells. In conclusion, these data indicate that ketamine injection induces voiding dysfunction in mice but does not necessarily disrupt mouse bladder barrier function. Disruption of urothelial barrier function may not be the major mechanism in ketamine cystitis.

Matched MeSH terms: Urothelium/pathology*; Urothelium/ultrastructure
Fulltext Overview of Urethral Reconstruction by Tissue Engineering: Current Strategies, Clinical Status and Future Direction

Rashidbenam Z, Jasman MH, Hafez P, Tan GH, Goh EH, Fam XI, et al.

Tissue Eng Regen Med, 2019 08;16(4):365-384.
PMID: 31413941 DOI: 10.1007/s13770-019-00193-z

BACKGROUND: Urinary tract is subjected to a variety of disorders such as urethral stricture, which often develops as a result of scarring process. Urethral stricture can be treated by urethral dilation and urethrotomy; but in cases of long urethral strictures, substitution urethroplasty with genital skin and buccal mucosa grafts is the only option. However a number of complications such as infection as a result of hair growth in neo-urethra, and stone formation restrict the application of those grafts. Therefore, tissue engineering techniques recently emerged as an alternative approach, aiming to overcome those restrictions. The aim of this review is to provide a comprehensive coverage on the strategies employed and the translational status of urethral tissue engineering over the past years and to propose a combinatory strategy for the future of urethral tissue engineering.
METHODs: Data collection was based on the key articles published in English language in years between 2006 and 2018 using the searching terms of urethral stricture and tissue engineering on PubMed database.
RESULTS: Differentiation of mesenchymal stem cells into urothelial and smooth muscle cells to be used for urologic application does not offer any advantage over autologous urothelial and smooth muscle cells. Among studied scaffolds, synthetic scaffolds with proper porosity and mechanical strength is the best option to be used for urethral tissue engineering.
CONCLUSION: Hypoxia-preconditioned mesenchymal stem cells in combination with autologous cells seeded on a pre-vascularized synthetic and biodegradable scaffold can be said to be the best combinatory strategy in engineering of human urethra.

Matched MeSH terms: Urothelium/surgery
Fulltext FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation

Foth M, Ismail NFB, Kung JSC, Tomlinson D, Knowles MA, Eriksson P, et al.

J Pathol, 2018 Nov;246(3):331-343.
PMID: 30043421 DOI: 10.1002/path.5143

Recent studies of muscle-invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH-BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH-BBN-driven tumours were increased in the presence of an S249C mutation compared to wild-type control mice. Interestingly, at an early tumour initiation stage, the acute inflammatory response in OH-BBN-treated bladders was suppressed in the presence of an S249C mutation. However, at later stages of tumour progression, increased inflammation was observed in S249C tumours, long after the carcinogen administration had ceased. Early-phase neutrophil depletion using an anti-Ly6G monoclonal antibody resulted in an increased neutrophil-to-lymphocyte ratio at later stages of pathogenesis, indicative of enhanced tumour pathogenesis, which supports the hypothesis that suppression of acute inflammation could play a causative role. Statistical analyses of correlation showed that while initial bladder phenotypes in morphology and inflammation were FGFR3-dependent, increased levels of inflammation were associated with tumour progression at the later stage. This study provides a novel insight into the tumour-promoting effect of FGFR3 mutations via regulation of inflammation at the pre-tumour stage in the bladder. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Matched MeSH terms: Urothelium
Fulltext Structural changes in the urinary bladder of streptozotocin-induced diabetic rats and the possible protective role of insulin

Elnagar, Amir M. Bassam, Suhaidah Ibrahim, Abouelnaga, Mostafa A.M., Soliman, Amro Mohamed

International Medical Journal Malaysia, 2018;17(3):39-48.
MyJurnal

Introduction: Diabetes mellitus possesses severe adverse effects on the urinary bladder. Urinary bladder dysfunction is a common health problem affecting diabetic patients causing recurrent infections and urinary incontinence. Objective: To evaluate the histopathological changes in the tissue of urinary bladder in Streptozotocin (STZ) diabetic rats and the protective role of insulin. Methods: Thirty rats were classified into three groups: a control group which received no treatment (Group A), STZ diabetic group (Group B) and Insulin diabetic group (Group C). Animals were sacrificed after six weeks and urinary bladders were harvested and processed for light and electron microscopy. Results: Several histopathological changes were observed in the urinary bladder of the diabetic group including an increase in the thickness of the urothelium, epithelial cells with dark nuclei and large lenticular vesicles, and wide intercellular spaces with numerous collagen fibers. Treatment with insulin reduced the pathological changes induced by STZ. Conclusion: Diabetes mellitus caused significant pathological changes in the urinary bladder of experimental rats. For instance, treating diabetic animals with insulin prevented the development of damaging effects of diabetes on the urinary bladder.

Matched MeSH terms: Urothelium
Fulltext Fabrication of Adipose-Derived Stem Cell-Based Self-Assembled Scaffold under Hypoxia and Mechanical Stimulation for Urethral Tissue Engineering

Rashidbenam Z, Jasman MH, Tan GH, Goh EH, Fam XI, Ho CCK, et al.

Int J Mol Sci, 2021 Mar 25;22(7).
PMID: 33805910 DOI: 10.3390/ijms22073350

Long urethral strictures are often treated with autologous genital skin and buccal mucosa grafts; however, risk of hair ingrowth and donor site morbidity, restrict their application. To overcome this, we introduced a tissue-engineered human urethra comprising adipose-derived stem cell (ASC)-based self-assembled scaffold, human urothelial cells (UCs) and smooth muscle cells (SMCs). ASCs were cultured with ascorbic acid to stimulate extracellular matrix (ECM) production. The scaffold (ECM) was stained with collagen type-I antibody and the thickness was measured under a confocal microscope. Results showed that the thickest scaffold (28.06 ± 0.59 μm) was achieved with 3 × 104 cells/cm2 seeding density, 100 μg/mL ascorbic acid concentration under hypoxic and dynamic culture condition. The biocompatibility assessment showed that UCs and SMCs seeded on the scaffold could proliferate and maintain the expression of their markers (CK7, CK20, UPIa, and UPII) and (α-SMA, MHC and Smootheline), respectively, after 14 days of in vitro culture. ECM gene expression analysis showed that the ASC and dermal fibroblast-based scaffolds (control) were comparable. The ASC-based scaffold can be handled and removed from the plate. This suggests that multiple layers of scaffold can be stacked to form the urothelium (seeded with UCs), submucosal layer (ASCs only), and smooth muscle layer (seeded with SMCs) and has the potential to be developed into a fully functional human urethra for urethral reconstructive surgeries.

Matched MeSH terms: Urothelium
PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells

Ismail AF, Oskay Halacli S, Babteen N, De Piano M, Martin TA, Jiang WG, et al.

Biochem. J., 2017 Mar 24;474(8):1333-1346.
PMID: 28232500 DOI: 10.1042/BCJ20160875

Urothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150 000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long-term prognosis. Thus, there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down-regulation of E-cadherin expression concomitant with a suppression of cell:cell junctions, and decreased levels of E-cadherin expression have been reported in higher grade urothelial bladder tumours. We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell:cell junctions and the level of PAK5 expression. Interestingly, exogenous PAK5 has recently been described to be associated with cell:cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that, in both our own patient samples and a commercially available dataset, PAK5mRNA levels are reduced in human bladder cancer compared with normal controls. Taken together, the present study proposes that PAK5 expression levels could be used as a novel prognostic marker for bladder cancer progression.

Matched MeSH terms: Urothelium/metabolism; Urothelium/pathology