Advances in the molecular pathogenesis and cell therapy of stress urinary incontinence

Abstract

Stress urinary incontinence (SUI) is very common in women. It affects patients' mental and physical health, and imposed huge socioeconomic pressure. The therapeutic effect of conservative treatment is limited, and depends heavily on patient persistence and compliance. Surgical treatment often brings procedure-related adverse complications and higher costs for patients. Therefore, it is necessary to better understand the potential molecular mechanisms underlying stress urinary incontinence and develop new treatment methods. Although some progress has been made in the basic research in recent years, the specific molecular pathogenic mechanisms of SUI are still unclear. Here, we reviewed the published studies on the molecular mechanisms associated with nerves, urethral muscles, periurethral connective tissue and hormones in the pathogenesis of SUI. In addition, we provide an update on the recent progresses in research on the use of cell therapy for treating SUI, including research on stem cells therapy, exosome differentiation and gene regulation.

Keywords: exosome differentiation; gene regulation; molecular pathogenesis; stem cell therapy; stress urinary incontinence.

FIGURE 1

Neuroregulation of micturition and neurogenic factors affecting SUI. The parasympathetic nerve stimulates the bladder detrusor muscle, mediated by muscarinic receptors (M2, M3) being activated by ACh. The sympathetic nerve stimulates urethral smooth muscle and inhibits bladder detrusor, mediated by α1-adrenergic and β3-adrenergic receptors, respectively. The somatic pudendal nerve stimulates striated muscle of the external urethral sphincter, mediated by ACh activating N receptors. BDNF binds to Trk receptors and p75NTR receptors to facilitate regeneration of pudendal nerve, but impair NMJ formation and myogenic myoblast differentiation and maturation. ACh: acetylcholine; EUS: external urethral sphincter; IUS: internal urethral sphincter; SUI: stress urinary incontinence; PMC: pontine micturition center; BDNF: brain-derived neurotrophic factor; Trk: tropomyosin receptor kinase; p75NTR: pan neurotrophin receptors; NMJ: neuromuscular junctions.

FIGURE 2

Molecules affecting urethral muscles in SUI. Vitamin D plays an important role in regulating muscle strength and function, and low serum vitamin D levels are associated with an increased risk of SUI; ANO1 is essential for maintaining the spontaneous tone of urethral smooth muscle; MSTN negatively regulated human urethral RS satellite cells proliferation and differentiation and TNF-α decreased the number of human urethral RS cells. EUS: external urethral sphincter; IUS: internal urethral sphincter; MSTN: myostatin; TNF-α: tumor necrosis factor-α; ANO1:anoctamin-1; SUI:stress urinary incontinence; RS: rhabdosphincter.

FIGURE 3

Molecules associated with connective tissue defect in SUI. Connective tissue, mainly contains collagen and elastic fibers, plays an important role in the continence mechanism. In the connective tissue of patients with SUI, collagen and elastic fibers were significantly reduced and damaged. MMP-1, TIMP-1, calpain-2, AQP2, miR-34a and ERK1/2 signaling pathway regulated the metabolism of collagen, and neutrophil elastase, α-1 antitrypsin, LOXL1, fibrillin-1 and TNF-β1/Smad regulated the metabolism of elastic fibers. EUS: external urethral sphincter; IUS: internal urethral sphincter; SUI: stress urinary incontinence; MMPs: matrix metalloproteinases; TIMPs: tissue inhibitors of metalloproteinases; AQPs: aquaporins; LOXL1:lysyl oxidase like-1; TNF-β1:Tumor necrosis factor-β1.

FIGURE 4

Stem cells in the treatment of SUI. The most widely used stem cells for stress urinary incontinence (SUI) are muscle-derived stem cells (MDSCs), adipose-derived stem cells (ADSCs), bone marrow hematopoietic stem cells (BMDSCs), amniotic fluid stem cells (AFSCs) and cord blood stem cells (CBSCs). After verifying the plasticity of stem cells, they are expanded to a certain number and injected into the urinary system. EUS: external urethral sphincter; IUS: internal urethral sphincter; SUI:stress urinary incontinence.