Mesenchymal stem cells and their secretome partially restore nerve and urethral function in a dual muscle and nerve injury stress urinary incontinence model

Abstract

Childbirth injures muscles and nerves responsible for urinary continence. Mesenchymal stem cells (MSCs) or their secretome given systemically could provide therapeutic benefit for this complex multisite injury. We investigated whether MSCs or their secretome, as collected from cell culture, facilitate recovery from simulated childbirth injury. Age-matched female Sprague-Dawley rats received pudendal nerve crush and vaginal distension (PNC+VD) and a single intravenous (iv) injection of 2 million MSCs or saline. Controls received sham injury and iv saline. Additional rats received PNC+VD and a single intraperitoneal (ip) injection of concentrated media conditioned by MSCs (CCM) or concentrated control media (CM). Controls received a sham injury and ip CM. Urethral and nerve function were assessed with leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings 3 wk after injury. Urethral and pudendal nerve anatomy were assessed qualitatively by blinded investigators. Quantitative data were analyzed using one-way ANOVA and Holm-Sidak post hoc tests with P < 0.05 indicating significant differences. Both LPP and PNSBP were significantly decreased 3 wk after PNC+VD with saline or CM compared with sham-injured rats, but not with MSC or CCM. Elastic fiber density in the urethra increased and changed in orientation after PNC+VD, with a greater increase in elastic fibers with MSC or CCM. Pudendal nerve fascicles were less dense and irregularly shaped after PNC+VD and had reduced pathology with MSC or CCM. MSC and CCM provide similar protective effects after PNC+VD, suggesting that MSCs act via their secretions in this dual muscle and nerve injury.

Smooth Muscle Precursor Cells Derived from Human Pluripotent Stem Cells for Treatment of Stress Urinary Incontinence

“…Bladder SMCs as a source of SMCs for bladder tissue regeneration has been studied [38][39][40][41]. The bladder SMCs and urothelial cells were reported to contribute to the development of bladder smooth muscle [42].…”

Smooth Muscle Progenitor Cells Derived From Human Pluripotent Stem Cells Induce Histologic Changes in Injured Urethral Sphincter

“…Various types of MSCs, isolated from bone marrow, skeletal muscle, and adipose tissue, have been tested for treatment of SUI, showing positive effects on urethral function in animals [14, 15] and safety and feasibility in humans [16, 17]. However, these adult stem cells are difficult to harvest and expand in vitro, especially in older patients.…”

“…Current data from animal models using animal autologous mesenchymal stem cells suggest that MSC/myoblasts/progenitor cells (mixed cell populations) exert their effect in vivo mostly through secretion of paracrine factors, rather than by significant cell replacement [15]. A few studies using human adult stem cell sources, amniotic fluid stem cell (SC)‐derived myocytes [19] and myoblasts from patient muscle biopsies [20], have suggested integration of muscle‐like cells in vivo.…”

Stem cells and lower urinary tract dysfunction: Has its potential finally reached clinical maturity? ICI‐RS2018

“…This suggests that the improvements in continence seen with AMDC in this animal model are due in part to their incorporation into the damaged urethral sphincter. In another rat model of SUI produced by both pudendal nerve crush and vaginal distention, both the intravenous injection of 2 million MSCs and the intraperitoneal delivery of the secretome produced by the SCs lead to similar levels of recovery and regeneration . Histology in those rats given either MSCs or secretome showed preservation and regeneration of the pudendal nerve, elastogenesis, and enhanced neuromuscular recovery.…”