Rapid differentiation of superficial urothelial cells after chitosan-induced desquamation

Veranič, Peter; Erman, Andreja; Kerec-Kos, Mojca; Bogataj, Marija; Mrhar, Aleš; Jezernik, Kristijan

doi:10.1007/s00418-008-0492-x

Cited by 47 publications

(54 citation statements)

References 42 publications

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“…4 In the normal urothelium, terminally differentiated superficial cells have an extremely long life time; 39,40 however, they are occasionally removed by exfoliation and the exfoliated areas are rapidly resealed. [41][42][43][44] In our study, we observed regions of exfoliated urothelium in control and in AuNPs-N animals, and in either case exfoliated regions were surrounded by differentiated, but smaller urothelial cells. In AuNPs-N animals, these cells contained nanoparticles indicating that what is observed are regenerating cells, which have not yet established a fully functional permeability barrier.…”

Section: Discussionsupporting

confidence: 56%

Gold nanoparticles as physiological markers of urine internalization into urothelial cells in vivo

Hudoklin¹,

Zupančič²,

Makovec³

et al. 2013

IJN

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Background: Urothelial bladder is the reservoir of urine and the urothelium minimizes the exchange of urine constituents with this tissue. Our aim was to test 1.9 nm biocompatible gold nanoparticles as a novel marker of internalization into the urothelial cells under physiological conditions in vivo. Methods: We compared normal and neoplastic mice urothelium. Neoplastic lesions were induced by 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water for 10 weeks. Nanoparticles, intravenously injected into normal and BBN-treated mice, were filtered through the kidneys and became constituents of the urine within 90 minutes after injection. Results: Gold nanoparticles were densely accumulated in the urine, while their internalization into urothelial cells depended on the cell differentiation stage. In the terminally differentiated superficial urothelial cells of normal animals, nanoparticles were occasionally found in the endosomes, but not in the fusiform vesicles. Regions of exfoliated cells were occasionally found in the normal urothelium. Superficial urothelial cells located next to exfoliated regions contained gold nanoparticles in the endosomes and in the cytosol beneath the apical plasma membrane. The urothelium of BBN-treated animals developed flat hyperplasia with moderate dysplasia. The superficial cells of BBN-treated animals were partially differentiated as demonstrated by the lack of fusiform vesicles. These cells contained the gold nanoparticles distributed in the endosomes and throughout their cytosol. Conclusion: Gold nanoparticles are a valuable marker to study urine internalization into urothelial cells in vivo. Moreover, they can be used as a sensitive marker of differentiation and functionality of urothelial cells.

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Section: Discussionsupporting

confidence: 56%

Gold nanoparticles as physiological markers of urine internalization into urothelial cells in vivo

Hudoklin¹,

Zupančič²,

Makovec³

et al. 2013

IJN

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“…The primary response of an injured urothelium is desquamation (Veranic and Jezernik 2000;Veranic et al 2009), necrosis (Lavelle et al 2002) and/or apoptosis of the UCs (Jezernik et al 2003). The secondary response is an enormous increase in proliferation of the remaining basal UCs (Hicks 1975).…”

Section: Introductionmentioning

confidence: 98%

Hyperplasia as a mechanism for rapid resealing urothelial injuries and maintaining high transepithelial resistance

Višnjar

Kocbek

Kreft

2011

Histochem Cell Biol

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When the urothelial barrier, i.e., the blood-urine barrier, is injured, rapid resealing of the injury is crucial for the normal functioning of the organism. In order to investigate the mechanisms required for rapid resealing of the barrier, we established in vitro models of hyperplastic and normoplastic urothelia. We found that hyperplastic urothelia achieve significantly higher transepithelial resistance (TER) than normoplastic urothelia. However, the expression of cell junctional (claudin-8, occludin, E-cadherin) and differentiation-related proteins (cytokeratin 20 and uroplakins) is weaker in hyperplastic urothelia. Further investigation of cell differentiation status at the ultrastructural level confirmed that superficial urothelial cells (UCs) in hyperplastic urothelial models achieve a lower differentiation stage than superficial UCs in normoplastic urothelial models. With the establishment of such in vitro models and the aid of TER measurements, flow cytometry, molecular and ultrastructural analysis, we here provide unequivocal evidence that the specific cell-cycle distribution and, consequently, the number of cell layers have a significant influence on the barrier function of urothelia. We demonstrate the importance of hyperplasia for the rapid restoration of the urothelial barrier and the maintenance of high TER until the UCs reach a highly differentiated stage and restoration of the urothelial barrier after injury is complete. The information that this approach provides is unique and we expect that further exploitation of hyperplastic and normoplastic urothelial models in future studies may advance our understanding of blood-urine barrier development and functionality.

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“…Our preliminary studies on the effects of HPGs on the urothelium have showed that HPG-C 8/10 -MePEG-NH 2 nanoparticles increase the permeability of the urinary bladder wall by causing changes to the urothelial barrier function and morphology through opening of tight junctions and exfoliation of the urothelium. These effects are similar to the effects on bladder mucosa caused by chitosan dispersions, a well-established, cationic, mucoadhesive polymer, which increased the permeability of isolated pig bladder to a model drug by causing desquamation of the urothelium (27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 61%

In vivo Evaluation of Mucoadhesive Nanoparticulate Docetaxel for Intravesical Treatment of Non–Muscle-Invasive Bladder Cancer

Mugabe

Matsui

et al. 2011

Clinical Cancer Research

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Purpose: The present work describes the development and in vitro and in vivo evaluation of a mucoadhesive nanoparticulate docetaxel (DTX) formulation for intravesical bladder cancer therapy.Experimental Design: Mucoadhesive formulations based on hyperbranched polyglycerols (HPG), hydrophobically derivatized with C 8 /C 10 alkyl chains in the core and modified with methoxy-polyethylene glycol (MePEG) and amine groups in the shell (HPG-C 8/10 -MePEG-NH 2 ) were synthesized and DTX was loaded into these by a solvent evaporation method. Both low-grade (RT4, MGHU3) and high-grade (UMUC3) human urothelial carcinoma cell lines were treated with various concentrations of DTX formulations in vitro. KU7 cells that stably express firefly luciferase (KU7-luc) were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU7-luc tumors were given a single intravesical instillation with PBS, Taxotere (DTX from Sanofiaventis), and DTX-loaded HPG-C 8/10 -MePEG and/or HPG-C 8/10 -MePEG-NH 2 . Drug uptake was conducted using LC/MS-MS (liquid chromatography/tandem mass spectrometry) and tumor microenvironment and uptake of rhodamine labeled HPGs was assessed.Results: In vitro, all DTX formulations potently inhibited bladder cancer proliferation. However, in vivo, DTX-loaded HPG-C 8/10 -MePEG-NH 2 (mucoadhesive DTX) was the most effective formulation to inhibit tumor growth in an orthotopic model of bladder cancer. Furthermore, mucoadhesive DTX significantly increased drug uptake in mouse bladder tissues. In addition, rhodamine labeled HPG-C 8/10 -MePEG-NH 2 showed enhanced uptake of these nanoparticles in bladder tumor tissues.Conclusions: Our data show promising in vivo antitumor efficacy and provide preclinical proof of principle for the intravesical application of mucoadhesive nanoparticulate DTX formulation in the treatment of bladder cancer. Clin Cancer Res; 17(9); 2788-98. Ó2011 AACR.

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Rapid differentiation of superficial urothelial cells after chitosan-induced desquamation

Cited by 47 publications

References 42 publications

Gold nanoparticles as physiological markers of urine internalization into urothelial cells in vivo

Gold nanoparticles as physiological markers of urine internalization into urothelial cells in vivo

Hyperplasia as a mechanism for rapid resealing urothelial injuries and maintaining high transepithelial resistance

In vivo Evaluation of Mucoadhesive Nanoparticulate Docetaxel for Intravesical Treatment of Non–Muscle-Invasive Bladder Cancer

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