Fabio Castiglione1, Karel Dewulf2, Lukman Hakim3, Emmanuel Weyne2, Francesco Montorsi4, Andrea Russo4, Luca Boeri4, Trinity J Bivalacqua5, Dirk De Ridder2, Steven Joniau2, Maarten Albersen6, Petter Hedlund7. 1. Laboratory for Experimental Urology, Organ Systems, Department of Development and Regeneration, University of Leuven, Leuven, Belgium; Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy. 2. Laboratory for Experimental Urology, Organ Systems, Department of Development and Regeneration, University of Leuven, Leuven, Belgium. 3. Laboratory for Experimental Urology, Organ Systems, Department of Development and Regeneration, University of Leuven, Leuven, Belgium; Department of Urology, Airlangga University/Dr. Soetomo General Hospital, Surabaya, Indonesia. 4. Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy. 5. The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA. 6. Laboratory for Experimental Urology, Organ Systems, Department of Development and Regeneration, University of Leuven, Leuven, Belgium. Electronic address: maarten.albersen@uzleuven.be. 7. Department of Clinical and Experimental Pharmacology, Lund University, Sweden; Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden.
Abstract
BACKGROUND: A medical treatment for urethral stricture (US) is not yet available. OBJECTIVE: To evaluate if local injection of human adipose tissue-derived stem cells (hADSC) prevents urethral fibrosis in a rat model of US. DESIGN, SETTING, AND PARTICIPANTS: Male rats were divided into three groups: sham, US, and hADSC (n=12 each). Sham rats received a vehicle injection in the urethral wall. US and hADSCs were incised and injected with the fibrosis-inducer transforming growth factor-β1 in the urethral wall. INTERVENTION: One day later, hADSCs were injected in the urethral wall of hADSC rats whereas sham and US rats were injected with the vehicle. After 4 wk, the rats underwent cystometries and tissues were then harvested for functional and molecular analyses. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cystometry, microultrasound, histochemistry, organ bath studies, reverse transcription polymerase chain reaction, and western blot. RESULTS AND LIMITATIONS: US rats exhibited 49-51% shorter micturition intervals, 35-51% smaller micturition volumes and bladder capacity, 33-62% higher threshold pressures and flow pressures, and 35-37% lower bladder filling compliance compared with hADSC-treated rats and sham rats (p<0.05). By ultrasound, US rats had hyperechogenic and thick urethral walls with narrowed lumen compared with sham rats, whereas hADSC rats displayed less extensive urethral changes. Isolated detrusor from US rats exhibited 34-55% smaller contractions than detrusor from sham rats (p<0.05). Corresponding values were 11-35% for isolated detrusors from hADSC rats. Collagen and elastin protein expression were increased in the penile urethras of US rats compared with sham and hADSC groups (p<0.05). Endothelial and inducible nitric oxide synthase expressions were higher (p<0.05) in the hADSC group. Compared with US rats, hADSC rats demonstrated decreased expression of several fibrosis-related genes. Administration of hADSCs was performed at an early stage of US development, which we consider a limitation of the study. CONCLUSIONS: Local injection of hADSCs prevents stricture formation and urodynamic complications in a new rat model for US. PATIENT SUMMARY: Stem cell therapy is effective for preventing urethral stricture in an experimental setting.
BACKGROUND: A medical treatment for urethral stricture (US) is not yet available. OBJECTIVE: To evaluate if local injection of human adipose tissue-derived stem cells (hADSC) prevents urethral fibrosis in a rat model of US. DESIGN, SETTING, AND PARTICIPANTS: Male rats were divided into three groups: sham, US, and hADSC (n=12 each). Sham rats received a vehicle injection in the urethral wall. US and hADSCs were incised and injected with the fibrosis-inducer transforming growth factor-β1 in the urethral wall. INTERVENTION: One day later, hADSCs were injected in the urethral wall of hADSC rats whereas sham and US rats were injected with the vehicle. After 4 wk, the rats underwent cystometries and tissues were then harvested for functional and molecular analyses. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cystometry, microultrasound, histochemistry, organ bath studies, reverse transcription polymerase chain reaction, and western blot. RESULTS AND LIMITATIONS: US rats exhibited 49-51% shorter micturition intervals, 35-51% smaller micturition volumes and bladder capacity, 33-62% higher threshold pressures and flow pressures, and 35-37% lower bladder filling compliance compared with hADSC-treated rats and sham rats (p<0.05). By ultrasound, US rats had hyperechogenic and thick urethral walls with narrowed lumen compared with sham rats, whereas hADSC rats displayed less extensive urethral changes. Isolated detrusor from US rats exhibited 34-55% smaller contractions than detrusor from sham rats (p<0.05). Corresponding values were 11-35% for isolated detrusors from hADSC rats. Collagen and elastin protein expression were increased in the penile urethras of US rats compared with sham and hADSC groups (p<0.05). Endothelial and inducible nitric oxide synthase expressions were higher (p<0.05) in the hADSC group. Compared with US rats, hADSC rats demonstrated decreased expression of several fibrosis-related genes. Administration of hADSCs was performed at an early stage of US development, which we consider a limitation of the study. CONCLUSIONS: Local injection of hADSCs prevents stricture formation and urodynamic complications in a new rat model for US. PATIENT SUMMARY: Stem cell therapy is effective for preventing urethral stricture in an experimental setting.
Authors: Juan José Rivera-Valdés; Jesus García-Bañuelos; Adriana Salazar-Montes; Leonel García-Benavides; Alfredo Dominguez-Rosales; Juan Armendáriz-Borunda; Ana Sandoval-Rodríguez Journal: PLoS One Date: 2017-12-27 Impact factor: 3.240
Authors: Marco Marcello; James W Denham; Angel Kennedy; Annette Haworth; Allison Steigler; Peter B Greer; Lois C Holloway; Jason A Dowling; Michael G Jameson; Dale Roach; David J Joseph; Sarah L Gulliford; David P Dearnaley; Matthew R Sydes; Emma Hall; Martin A Ebert Journal: Front Oncol Date: 2020-07-22 Impact factor: 6.244