Co-transplantation of two different cell populations: A novel step forward to address stress urinary incontinence (SUI)

The involuntary leakage of urine during physical activity or effort is known as stress urinary incontinence (SUI). To achieve continence, a functioning urethral sphincter complex is necessary. SUI is more predominant in females. Hypermobility of the urethra and/or a lack of intrinsic sphincters in females can lead to SUI. Age, Caucasian race, obesity, smoking, and vaginal delivery are six risk factors [1]. Comparatively, in men, the most common reason for SUI is dysfunction of the urethral sphincter following prostate surgery, which leads to a decrease in the number of striated and smooth muscle cells, poor blood flow, and denervation of the sphincter. SUI is managed in a step-by-step manner. In women, the conservative approach to treatment includes lifestyle changes such as quitting smoking and losing weight, pelvic floor muscle training, and electrical stimulation of the pelvic floor. Duloxetine is used as a medical treatment, although it is not widely accepted due to worries about side effects, particularly the rate of suicide. An artificial urethral sphincter, colpo-suspension, midurethral slings, pubovaginal slings, tension-free vaginal tape, transobturator tape, and urethral bulking agents are available for patients who need surgical therapy [2,3]. In men, pelvic floor training, biofeedback, electrostimulation, pharmacotherapy, paraurethral injection of bulking agents, sling-plasties and implantation of artificial sphincter systems are available, but more effective treatments are needed [4]. Some positive outcomes have been reported with cell-based therapies such as autologous adipose-derived stem cells (ADSC) and autologous muscle-derived stem cells (MDSC) [1]. Variability in stem cell type, dose, results, and potential for malignant transformation, especially in men who have SUI after prostate cancer surgery, are hurdles that mar the routine clinical application of cell therapies for SUI [3].

In the current issue of JSRM, Daneshpajooh et al [5] report the therapeutic effect of periurethral injection of MDSC and fibroblasts versus mid-urethral sling surgery in 30 women with SUI. This is a one-of-a-kind study in which two different cell populations are in vitro cultured and mixed together followed by transplantation for SUI. Their results showed that though cell therapy improves the symptoms, mid-urethral sling injury seems to offer a better therapeutic response. Dr. Horiguchi’s editorial comment on this article [6] also suggests that mid-urethral slings have a higher success rate and are now considered the standard of care, but due to associated complications such as vaginal mesh extrusions, mesh perforation at the bladder and urethra, urinary retention, pelvic and groin pain, and dyspareunia warrant the need for an alternate or complementary approach including cell based therapies applicable in both men and women but with further improvisation for better effectiveness.

Based on the above background, if we consider a cell-based therapy for SUI, fibroblast to myofibroblast conversion is essential during the regenerative-healing process for the sphincter to be effective in preventing the leakage [3]. However, myofibroblast conversion is a double-edged sword as the underlying hurdle of over-proliferation is a major issue, especially related to malignant transformation as well as fibrosis leading to urinary obstruction [3,7,8]. Earlier, myofibroblast over-proliferation was reported as the key pathological mechanism of urethral stricture in men [9] which has been postulated to be potentially addressed by controlled myofibroblast proliferation using techniques such as cell therapies that involve TGF-beta, IGF release scaffolds, BEES-HAUS [10-14], etc. Therefore, in-depth exploration of cell therapies is critical to improving the efficacy and standardization of these therapies for SUI—especially in characterizing different types of cells used in therapeutic applications, their specific contribution to the process of healing such as factors or cytokines produced by each cell type, validation of such outcomes in relevant basic and translational studies pertaining to the optimal proliferation of myofibroblasts in the case of SUI. This co-transplantation—wherein two different cell populations complement each other in resolving a damaged sphincter system by contributing to muscle regeneration when standardized—may help with other pathologies involving epithelial damage, compromised myofibroblast proliferation, weak muscles and relevant fibrosis.