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 × 106) 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.
Highlights
Administration of mesenchymal stem/stromal cells (MSCs) was found to stimulate the regeneration of damaged tissues and secrete growth factors and cytokines that promote angiogenesis and cell survival and prevent apoptosis of damaged tissues in several intractable disorders[11,12,13,14,15,16]
We recently reported that daily injection of rats with ketamine for 2 week can induce the pathology seen in the Ketamine-induced cystitis (KC) bladder[30]
Using this KC animal model, we first examined whether MSC transplantation could ameliorate the defective voiding function of the KC bladder by performing conscious cystometric analysis, which monitors the ability of the bladder to contract and expel urine (Fig. 1)
Summary
Administration of mesenchymal stem/stromal cells (MSCs) was found to stimulate the regeneration of damaged tissues and secrete growth factors and cytokines that promote angiogenesis and cell survival and prevent apoptosis of damaged tissues in several intractable disorders[11,12,13,14,15,16]. MSCs are adult multipotent progenitor cells derived from a variety of adult tissues (eg, bone marrow, adipose, peripheral blood, and dental pulp) and fetal ones (eg, umbilical cord blood [UCB], Wharton’s jelly, placenta, and amniotic fluid)[13,14,15,17,18]. They can differentiate into several lineages (osteoblasts, chondrocytes, and adipocytes), and potentially other lineages including epithelial cells. Using a rat KC animal model, we provide, for the first time, experimental evidence that MSC therapy helps to reverse the IC-like symptoms of KC
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