Progress of mesenchymal stem cells affecting extracellular matrix metabolism in the treatment of female stress urinary incontinence

Abstract

Stress urinary incontinence (SUI) is a prevalent pelvic floor dysfunction in women post-pregnancy. Currently, conservative treatment options have low success rates, while surgical interventions often result in multiple complications. The altered state of the extracellular matrix (ECM) is a pivotal factor in the onset of various diseases and likely plays a significant role in the pathogenesis of SUI, particularly through changes in collagen and elastin levels. Recent advances in mesenchymal stem cells (MSCs) therapy have shown considerable promise in treating SUI by modulating ECM remodeling, thereby enhancing the supportive tissues of the female pelvic floor. MSCs exhibit substantial potential in enhancing urethral sphincter function, modulating connective tissue architecture, and stimulating fibroblast activity. They play a pivotal role in the reconstruction and functional recovery of the ECM by influencing various signaling pathways, including TGF-β/SMAD, JAK/STAT, Wnt/β-catenin, PI3K/AKT, and ERK/MAPK. We have reviewed the advancements in MSC-mediated ECM metabolism in SUI and, by integrating the functions of ECM in other diseases and how MSCs can ameliorate conditions through their impact on ECM metabolism, we have projected the future trajectory of SUI treatment development.

Keywords: Collagen; Connective tissue; Elastin; Extracellular matrix; Fibroblasts; Mesenchymal stem cells; Signaling pathways; Stress urinary incontinence.

Fig. 1

Remodeling of pelvic floor support tissue ECM by MSCs from different tissue sources

Fig. 2

MSCs regulate fibroblasts through paracrine effects. After MSCs-secreted EVs and Exos are internalized by fibroblasts, their loads of miR-93, miR-328-3p, and other substances regulate fibroblast remodeling of the ECM

Fig. 3

Signaling pathways of MSCs-driven intracellular ECM. Signaling pathways of MSCs-driven intracellular ECM. In the TGF-β/SMAD pathway, BMSCs-EVs load miR-328a-3p into fibroblasts. miR-328a-3p downregulates SIRT7 expression, which in turn promotes the binding of phosphorylated SMAD2/3 to SMAD4 into the nucleus and promotes the expression of elastin, collagen I, and III. In the JAK/STAT pathway, cytokines and GFs secreted by BMSCs bind to target cell receptors and activate JAK2-STAT4 phosphorylation, and p-STAT4 forms a dimer to enter the nucleus and promote collagen I and III expression. In the Wnt/β-catenin pathway, miR-3960 loaded by MSCs-EVs entered the target cells and down-regulated PHLDA2, inhibiting ECM degradation induced by this substance. In the PI3K/AKT pathway, IGF-1 secreted by MSCs activated PI3K-AKT-mTOR phosphorylation and regulated intracytoplasmic protein synthesis. In the ERK/MAPK pathway, VEGF secreted by MSCs can activate Ras-Raf-MEK-ERK1/2 phosphorylation, which promotes the expression of collagen I and III in the nucleus and regulates protein synthesis in the cytoplasm