Mesenchymal stem cells protect against the tissue fibrosis of ketamine-induced cystitis in rat bladder

Sci Rep. 2016 Aug 2;6:30881. doi: 10.1038/srep30881.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / toxicity
  • Animals
  • Cells, Cultured
  • Cystitis / chemically induced
  • Cystitis / therapy*
  • Disease Models, Animal
  • Fibrosis / etiology
  • Fibrosis / therapy*
  • Humans
  • Infant, Newborn
  • Ketamine / toxicity*
  • Male
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology*
  • Protective Agents
  • Rats
  • Rats, Sprague-Dawley
  • Urinary Bladder / physiopathology*

Substances

  • Analgesics
  • Protective Agents
  • Ketamine