title: Mesenchymal stem cells protect against the tissue fibrosis of ketamine-induced cystitis in rat bladder.
abstract: Abuse of the hallucinogenic drug ketamine promotes the development of lower urinary tract symptoms that resemble interstitial cystitis. The pathophysiology of ketamine-induced cystitis (KC) is largely unknown and effective therapies are lacking. Here, using a KC rat model, we show the therapeutic effects of human umbilical cord-blood (UCB)-derived mesenchymal stem cells (MSCs). Daily injection of ketamine to Sprague-Dawley rats for 2-weeks resulted in defective bladder function, indicated by irregular voiding frequency, increased maximum contraction pressure, and decreased intercontraction intervals and bladder capacity. KC bladders were characterized by severe mast-cell infiltration, tissue fibrosis, apoptosis, upregulation of transforming growth factor-β signaling related genes, and phosphorylation of Smad2 and Smad3 proteins. A single administration of MSCs (1 × 10(6)) into bladder tissue not only significantly ameliorated the aforementioned bladder voiding parameters, but also reversed the characteristic histological and gene-expression alterations of KC bladder. Treatment with the antifibrotic compound N-acetylcysteine also alleviated the symptoms and pathological characteristics of KC bladder, indicating that the antifibrotic capacity of MSC therapy underlies its benefits. Thus, this study for the first-time shows that MSC therapy might help to cure KC by protecting against tissue fibrosis in a KC animal model and provides a foundation for clinical trials of MSC therapy.
authors.affiliation: Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Aram
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.|Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Hwan Yeul
authors.initials: HY
authors.lastname: Yu
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.|Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Jinbeom
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Miho
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.|Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Jisun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.|Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Soo-Jung
authors.initials: SJ
authors.lastname: Yoon
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.|Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: YongHwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.|Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Seungun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si, Gyeonggi-do, 13494, Korea.
authors.forename: Wonil
authors.initials: W
authors.lastname: Oh
authors.affiliation: Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si, Gyeonggi-do, 13494, Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.|Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Myung-Soo
authors.initials: MS
authors.lastname: Choo
mesh_terms: D000700:Analgesics / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D003556:Cystitis / Q000139:chemically induced / Q000628:therapy*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology / Q000628:therapy*; D006801:Humans; D007231:Infant, Newborn; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D020011:Protective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000503:physiopathology*
chemical_list: D000700:Analgesics; D020011:Protective Agents; D007649:Ketamine