Multiple doses of stem cells maintain urethral function in a model of neuromuscular injury resulting in stress urinary incontinence

Abstract

Stress urinary incontinence (SUI) is more prevalent among women who deliver vaginally than women who have had a cesarean section, suggesting that tissue repair after vaginal delivery is insufficient. A single dose of mesenchymal stem cells (MSCs) has been shown to partially restore urethral function in a model of SUI. The aim of the present study was to determine if increasing the number of doses of MSCs improves urethral and pudendal nerve function and anatomy. We hypothesized that increasing the number of MSC doses would accelerate recovery from SUI compared with vehicle treatment. Rats underwent pudendal nerve crush and vaginal distension or a sham injury and were treated intravenously with vehicle or one, two, or three doses of 2 × 106 MSCs at 1 h, 7 days, and 14 days after injury. Urethral leak point pressure testing with simultaneous external urethral sphincter electromyography and pudendal nerve electroneurography were performed 21 days after injury, and the urethrovaginal complex and pudendal nerve were harvested for semiquantitative morphometry of the external urethral sphincter, urethral elastin, and pudendal nerve. Two and three doses of MSCs significantly improved peak pressure; however, a single dose of MSCs did not. Single, as well as repeated, MSC doses improved urethral integrity by restoring urethral connective tissue composition and neuromuscular structures. MSC treatment improved elastogenesis, prevented disruption of the external urethral sphincter, and enhanced pudendal nerve morphology. These results suggest that MSC therapy for postpartum incontinence and SUI can be enhanced with multiple doses.

Novel Techniques to Improve Precise Cell Injection

“…Replacing needle injections by water-jet application of cells may reduce the costs for cell production when fewer cells are injected more precisely, avoiding loss of cells by reflux or full penetration [42]. The fewer cells injected by water-jet close to the sphincter muscle may even yield a comparable or even better outcome when compared to multiple injections of more cells by needle in one session, increasing the risk of injury considerably [49,62] or in repeated sections over time, which raises other concerns [63].…”

Cell Technologies in the Stress Urinary Incontinence Correction

“…Single as well as repeated doses of 2 × 10 6 MSCs 1 h, 7 days, and 14 days after vaginal distension and crushing n. pudendus in rats improved the integrity of the urethra, restoring the composition of its connective tissue and neuromuscular structures. MSC treatment improved elastogenesis, prevented dysfunction of the external urethral sphincter, and restored the n. pudendus morphology [ 7 ].…”

“…Standard therapies often provide symptomatic relief, but do not target against the underlying etiology, and exhibit tremendous patient-to-patient variability of results, limited success, and procedure-related complications. More clinical trials of new treatment methods involving the required number of patients and with evaluation the long-term results of therapeutic methods for the incontinence correction should be encouraged [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].…”

Treatment of Stress Urinary Incontinence with Muscle Stem Cells and Stem Cell Components: Chances, Challenges and Future Prospects

“…This is critical for translating a promising achievement from the laboratory bench to the patient’s bedside, and later into a specific treatment of clinical daily routine [ 50 ]. Many studies have explored the preclinical and clinical application of stem cells isolated from various origins that have promising results for the treatment of SUI [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ] and were summoned up as part of the several reviews articles. Hart and colleagues summarized the mainly preclinical published literature on cell therapy models for the regeneration of smooth and striated urethral sphincter muscles, but also the regeneration of nerves and neuromuscular synapses [ 47 ].…”