Miho Song

The Paracrine Effects of Mesenchymal Stem Cells Stimulate the Regeneration Capacity of Endogenous Stem Cells in the Repair of a Bladder-Outlet-Obstruction-Induced Overactive Bladder

Overactive bladder (OAB), which is characterized by the sudden and uncomfortable need to urinate with or without urinary leakage, is a challenging urological condition. The insufficient efficacy of current pharmacotherapies that uses antimuscarinic agents has increased the demand for novel long-term/stable therapeutic strategies. Here, we report the superior therapeutic efficacy of using mesenchymal stem cells (MSCs) for the treatment of OAB and a novel therapeutic mechanism that activates endogenous Oct4(+) primitive stem cells. We induced OAB using bladder-outlet-obstruction (BOO) in a rat model and either administered a single transplantation of human adipose-derived MSCs or daily intravenous injections of solifenacin, an antimuscarinic agent, for 2 weeks. Within 2 weeks, both the MSC- and solifenacin-treated groups similarly demonstrated relief from BOO-induced detrusor overactivity, hypertrophic smooth muscle, and neurological injuries. In contrast with the solifenacin-treated groups, a single transplantation of MSCs improved most OAB parameters to normal levels within 4 weeks. Although the transplanted human MSCs were hardly engrafted into the damaged bladders, the bladder tissues transplanted with MSCs increased rat sequence-specific transcription of Oct4, Sox2, and Stella, which are surrogate markers for primitive pluripotent stem cells. In addition, MSCs enhanced the expression of several genes, responsible for stem cell trafficking, including SDF-1/CXCR4, HGF/cMet, PDGF/PDGFR, and VEGF/VEGFR signaling axis. These changes in gene expression were not observed in the solifenacin-treated group. Therefore, we suggest the novel mechanisms for the paracrine effect of MSCs as unleashing/mobilizing primitive endogenous stem cells, which could not only explain the long-term/stable therapeutic efficacy of MSCs, but also provide promising new therapies for the treatment of OAB.

Mesenchymal Stem Cell Therapy Alleviates Interstitial Cystitis by Activating Wnt Signaling Pathway

Interstitial cystitis (IC) is a syndrome characterized by urinary urgency, frequency, pelvic pain, and nocturia in the absence of bacterial infection or identifiable pathology. IC is a devastating disease that certainly decreases quality of life. However, the causes of IC remain unknown and no effective treatments or cures have been developed. This study evaluated the therapeutic potency of using human umbilical cord-blood-derived mesenchymal stem cells (UCB-MSCs) to treat IC in a rat model and to investigate its responsible molecular mechanism. IC was induced in 10-week-old female Sprague-Dawley rats via the instillation of 0.1 M HCl or phosphate-buffered saline (PBS; sham). After 1 week, human UCB-MSC (IC+MSC) or PBS (IC) was directly injected into the submucosal layer of the bladder. A single injection of human UCB-MSCs significantly attenuated the irregular and decreased voiding interval in the IC group. Accordingly, denudation of the epithelium and increased inflammatory responses, mast cell infiltration, neurofilament production, and angiogenesis observed in the IC bladders were prevented in the IC+MSC group. The injected UCB-MSCs successfully engrafted to the stromal and epithelial tissues and activated Wnt signaling cascade. Interference with Wnt and epidermal growth factor receptor activity by small molecules abrogated the benefits of MSC therapy. This is the first report that provides an experimental evidence of the therapeutic effects and molecular mechanisms of MSC therapy to IC using an orthodox rat animal model. Our findings not only provide the basis for clinical trials of MSC therapy to IC but also advance our understanding of IC pathophysiology.

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

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.

The efficacy and tolerability of tarafenacin, a new muscarinic acetylcholine receptor M3 antagonist in patients with overactive bladder; randomised, double-blind, placebo-controlled phase 2 study

To evaluate the dose–response relationship of tarafenacin, an antimuscarinic agent in development phase, for efficacy and safety, at daily doses of 0.2 and 0.4 mg for the treatment of overactive bladder (OAB)

Comparing Argus sling and artificial urinary sphincter in patients with moderate post-prostatectomy incontinence

Post-prostatectomy incontinence (PPI) is a main complication of radical prostatectomy. The purpose of this study was to compare the efficacy and safety of the Argus male sling (Argus) with that of artificial urinary sphincters (AUS) in patients with moderate PPI. A total of 33 moderate PPI patients underwent AUS or Argus implantation from January 2009 to June 2013 (13 AUS, 20 Argus). We defined moderate PPI as the use of 2–4 pads per day. To compare efficacy, we assessed the success rate between the two groups. Success was defined as the daily need for no pads or one small safety pad that remained dry most of the day. The mean patient age was 73.5±6.3 yr in the AUS group and 70.9±5.1 yr in the Argus group, and the mean follow-up period was 29.8±14.9 months in the AUS group and 24.7±11.8 months in the Argus group. The success rate was 72.7% in the AUS group and 85.0% in the Argus group (P=0.557). Abnormal postoperative pain persisted in more patients in the Argus group (6/20, 30%) than in the AUS group (1/13, 7.7%) (P=0.126). However, the rate of other complications was not different between the two groups (7.7% and 15.0% for AUS and Argus, respectively, P=0.822). Argus surgery showed similar success and complication rates to those of AUS in moderate PPI patients, indicating that it could be an alternative surgical option for the treatment of moderate PPI.

Safety and efficacy of 8-mg once-daily vs 4-mg twice-daily silodosin in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (SILVER Study): a 12-week, double-blind, randomized, parallel, multicenter study.

OBJECTIVE To show the noninferiority of silodosin 8-mg once-daily (QD) to 4-mg twice-daily (BID) in efficacy and safety in patients with lower urinary tract symptoms or benign prostatic hyperplasia in the Korean population. METHODS A prospective, multicenter, double-blind, randomized, comparative study was conducted. A total of 532 male patients aged ≥50 years with lower urinary tract symptoms or benign prostatic hyperplasia were included. All patients received silodosin QD or BID for 12 weeks. The primary end point was the change from baseline in total International Prostate Symptom Score (IPSS) at 12 weeks. Adverse drug reactions, vital signs, and laboratory tests were recorded. RESULTS A total of 424 patients were randomized to the silodosin QD or BID groups. These groups were not significantly different in baseline characteristics. The mean total IPSS change in QD group was not inferior to that in BID group (-6.70 and -6.94, respectively; 95% confidence interval, -0.88 to 1.36). The QD and BID groups did not significantly differ in the following: percentages of patients with ≥25% (63.41% and 67.82%, respectively; P = .349) or ≥4-point improvement in total IPSS (65.85% and 69.31%, respectively; P = .457), maximum urinary flow rate improvement ≥30% (47.32% and 40.59%, respectively; P = .172), changes in IPSS voiding subscore (-4.42 ± 4.93 and -4.65 ± 4.77; P = .641), IPSS storage subscore (-2.05 ± 3.07 and -2.52 ± 2.97; P = .117), quality of life (-1.19 ± 1.49 and -1.40 ± 1.42; P = .136), maximum urinary flow rate (3.55 ± 5.93 and 3.74 ± 6.79 mL/s; P = .768), International Continence Society male questionnaire score, Patient Goal Achievement Score, or Treatment Satisfaction Question. The 2 groups had similar frequencies of adverse drug reactions. CONCLUSION QD administration of silodosin was not inferior to BID in efficacy. The 2 groups had similar adverse drug reaction profiles.

A Comparative Study of Outside-In and Inside-Out Transobturator Tape Procedures for Female Stress Urinary Incontinence: 7-Year Outcomes.

The aim of this study was to compare the long‐term surgical outcomes of the “inside‐out” (TVT‐O) and “outside‐in” (TOT) transobturator tape procedures for treating female stress urinary incontinence (SUI).

Improved efficacy and in vivo cellular properties of human embryonic stem cell derivative in a preclinical model of bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease characterized by severe pelvic pain and urinary frequency. Mesenchymal stem cell (MSC) therapy is a promising approach to treat incurable IC/BPS. Here, we show greater therapeutic efficacy of human embryonic stem cell (hESC)-derived multipotent stem cells (M-MSCs) than adult bone-marrow (BM)-derived counterparts for treating IC/BPS and also monitor long-term safety and in vivo properties of transplanted M-MSCs in living animals. Controlled hESC differentiation and isolation procedures resulted in pure M-MSCs displaying typical MSC behavior. In a hydrochloric-acid instillation-induced IC/BPS animal model, a single local injection of M-MSCs ameliorated bladder symptoms of IC/BPS with superior efficacy compared to BM-derived MSCs in ameliorating bladder voiding function and histological injuries including urothelium denudation, mast-cell infiltration, tissue fibrosis, apoptosis, and visceral hypersensitivity. Little adverse outcomes such as abnormal growth, tumorigenesis, or immune-mediated transplant rejection were observed over 12-months post-injection. Intravital confocal fluorescence imaging tracked the persistence of the transplanted cells over 6-months in living animals. The infused M-MSCs differentiated into multiple cell types and gradually integrated into vascular-like structures. The present study provides the first evidence for improved therapeutic efficacy, long-term safety, and in vivo distribution and cellular properties of hESC derivatives in preclinical models of IC/BPS.

Clinical Factors Associated With Dose Escalation of Solifenacin for the Treatment of Overactive Bladder in Real Life Practice

Purpose To determine the baseline clinical characteristics associated with dose escalation of solifenacin in patients with overactive bladder (OAB). Methods We analyzed the data of patients with OAB (micturition frequency ≥8/day and urgency ≥1/day) who were treated with solifenacin and followed up for 24 weeks. According to our department protocol, all the patients kept voiding diaries, and OAB symptom scores (OABSS) were monitored at baseline and after 4, 12, and 24 weeks of solifenacin treatment. Results In total, 68 patients (mean age, 60.8±10.0 years) were recruited. The dose escalation rate by the end of the study was 41.2%, from 23.5% at 4 weeks and 17.6% at 12 weeks. At baseline, the dose escalator group had significantly more OAB wet patients (53.6% vs. 20.0%) and higher total OABSS (10.2±2.4 vs. 7.9±3.5, P=0.032) than the nonescalator group. OAB wet (odds ratio [OR], 4.615; 95% confidence interval [CI], 1.578-13.499; P<0.05) and total OABSS (OR, 1.398; 95% CI, 1.046-1.869; P<0.05) were found to be independently associated with dose escalation. Conclusions Patients who have urgency urinary incontinence and high total OABSS have a tendency for dose escalation of solifenacin.

Correlation of the Overactive Bladder Symptom Score, and the Voiding Diary and Urodynamic Parameters in Patients with Overactive Bladder Syndrome

To investigate correlations between the overactive bladder symptom score (OABSS), the voiding diary, and urodynamic parameters in women with overactive bladder syndrome (OAB).