Stress urinary incontinence (SUI) is defined by the International Continence Society (ICS) [1] as the involuntary and uncontrolled urine excretion on a sudden increase in abdominal pressure (such as exertion, physical activity, sneezing, or coughing, etc.). At the 6th International Urinary Control Forum [2, 3], a global epidemiological survey of SUI pointed out that 25–45% of women have had urinary incontinence, 50% of which are SUI. Because many women with SUI are reluctant to admit the disease or even seek medical attention negatively, the actual incidence of female SUI may reach more than 80%.
Conservative management or surgery is usually applied in the treatment of SUI [4]. The former is often used for the frail elderly patients or patients with mild or moderate SUI but unwilling to receive surgery. Conservative management includes weight loss, pelvic floor muscle training (PFMT), drug therapy represented by estrogen, electrical stimulation therapy, intravaginal devices. This treatment has been shown to be beneficial, but it is required good compliance of patients. Surgery, at present, is still recommended as first-line treatment for severe SUI patients with obvious symptoms or patients fail to conservative management. Surgery can restore the normal physiological anatomy of urethra or simulates its mechanical structure as much as possible, at least the anatomy and functional reconstruction of the middle and upper urethra. In addition, the therapeutic filler can also be injected into the bladder neck, middle and upper urethra or periurethral structural tissues (such as anterior vaginal wall) of patients through urethra or vagina, so as to reduce the urethral lumen of SUI patients, thereby increasing the resistance of posterior urethra, prolonging the length of functional urethra and improving urinary continence. The existing research results have revealed that surgery has higher success rate in the treatment of SUI compared with the injection therapy, but the corresponding complication rate of surgery is also higher. The development of urethral filler and injection therapy for SUI is rapid, and this treatment has good short-term results but poor long-term effect, with various side effects [5].
Regenerative medicine [2] usually refers to the use of biological and engineering methods to re-create and repair tissues and organs with functional injury or loss, which makes modern medicine treatment gradually developing towards repairing, reconstructing, replacing damaged organ tissues. Stem cells can differentiate into a range of cell types and have the ability to continuously self-renew and self-sustenance. They can differentiate into progenitor cells to replace apoptotic senescent cells [6]. Due to the poor long-term effect of urethral filler injection, another therapeutic approach have attracted interest of academia, which refer to the reconstruction of urethral sphincter function in SUI patients using the regenerative characteristics of stem cells regenerative, thus promoting many related animal experiments[7–10]. In these studies, mesenchymal stem cells (MSCs), a source of cells, are usually derived from muscle, adipose tissue, or bone marrow tissue [11]. Regardless of where they derived from, MSCs share some common characteristics, such as stable replication potential and self-renew ability, as well as multipotential differentiation. Studies have shown that MSCs is important in SUI repair. For example, Jacques Corcos [12] showed that intrasphincteric injection of MSCs improves repair the damaged external urethral sphincter and had therapeutic effects on animal models of SUI. Stem cells derived from different tissues have their own advantages and disadvantages. For example, muscle-derived stem cells (MDSCs) have a wide range of sources, are easy to obtain, with mature in vitro amplification techniques. Meanwhile, transplant immune rejection of MDSCs has been solved. Muscle fibers obtained after differentiation of MDSCs automatically integrate into the patient's muscle cell group, avoiding the allergic reaction after MDSCs transplantation; and because the low expression of MHC-1, the incidence of immune rejection is further reduced [13–15].
Nerve growth factor (NGF) [16] is a protein with a molecular weight of about 140,000, which plays an important role in regulating the growth, differentiation and regeneration of nerve cells. With the deepening of research, NGF has found to have biological effects on non-neural cells [17, 18], such as promoting the formation of new blood vessels [19], guiding the cell differentiation of damaged muscle spindles [20], and promoting the repair of fibroblasts in the skin, lung and other parts. In addition, it has been found that NGF is also able to promote the differentiation of stem cells [21], which provides a theoretical basis for NGF combined with stem cell transplantation in the treatment of related diseases. Based on these findings, rat models of SUI was constructed in this study to investigate the efficacy of MDSCs combined with NGF in the treatment of SUI, as well as the repair of leak point pressure (LPP) and urethral smooth muscle in rats, so as to explore the application prospect of MDSCs in the treatment of SUI.