Charuspong Dissaranan

Pelvic organ distribution of mesenchymal stem cells injected intravenously after simulated childbirth injury in female rats.

The local route of stem cell administration utilized presently in clinical trials for stress incontinence may not take full advantage of the capabilities of these cells. The goal of this study was to evaluate if intravenously injected mesenchymal stem cells (MSCs) home to pelvic organs after simulated childbirth injury in a rat model. Female rats underwent either vaginal distension (VD) or sham VD. All rats received 2 million GFP-labeled MSCs intravenously 1 hour after injury. Four or 10 days later pelvic organs and muscles were imaged for visualization of GFP-positive cells. Significantly more MSCs home to the urethra, vagina, rectum, and levator ani muscle 4 days after VD than after sham VD. MSCs were present 10 days after injection but GFP intensity had decreased. This study provides basic science evidence that intravenous administration of MSCs could provide an effective route for cell-based therapy to facilitate repair after injury and treat stress incontinence.

Rat mesenchymal stem cell secretome promotes elastogenesis and facilitates recovery from simulated childbirth injury.

Vaginal delivery is a risk factor for stress urinary incontinence (SUI). Mesenchymal stem cells (MSCs) home to injured organs and can facilitate repair. The goal of this study was to determine if MSCs home to pelvic organs after simulated childbirth injury and facilitate recovery from SUI via paracrine factors. Three experiments were performed. Eighteen female rats received vaginal distension (VD) or sham VD and labeled intravenous (IV) MSCs to investigate if MSCs home to the pelvic organs. Whole-organ imaging and immunofluorescence were performed 1 week later. Thirty-four female rats received VD and IV MSCs, VD and IV saline, or sham VD and IV saline to investigate if MSCs accelerate recovery of continence. Twenty-nine female rats received VD and periurethral concentrated conditioned media (CCM), VD and periurethral control media, or sham VD and periurethral control media to investigate if factors secreted by MSCs accelerate recovery from VD. Urethral histology and function were assessed 1 week later. Significantly more MSCs were observed in the urethra, vagina, and spleen after VD compared to sham VD. Continence as measured by leak point pressure (LPP) was significantly reduced after VD in rats treated with saline or control media compared to sham VD but not in those given MSCs or CCM. External urethral sphincter (EUS) function as measured by electromyography (EMG) was not improved with MSCs or CCM. Rats treated with MSCs or CCM demonstrated an increase in elastin fibers near the EUS and urethral smooth muscle more similar to that of sham-injured animals than rats treated with saline or control media. MSCs homed to the urethra and vagina and facilitated recovery of continence most likely via secretion of paracrine factors. Both MSCs and CCM have promise as novel noninvasive therapies for SUI.

Stem Cell Therapy for Incontinence: Where Are We Now? What is the Realistic Potential?

A significant number of women experience stress urinary incontinence (SUI), which greatly affects their quality of life. Recent research investigating utilization of stem cells and their derivatives for the prevention and treatment of SUI has been performed to test the effect of cell source and method of administration in several animal models of SUI. The type of stem cell, timing of optimal dose or doses after injury, mechanism of action of stem cells, and route of administration must be investigated both preclinically and clinically before stem cell therapy becomes a possible treatment for SUI, although the future of this therapy looks promising. This article reviews the progress in stem cell research for incontinence and describes areas of future work as suggested by research in other fields.

Effects of acute selective pudendal nerve electrical stimulation after simulated childbirth injury

During childbirth, a combinatorial injury occurs and can result in stress urinary incontinence (SUI). Simulated childbirth injury, consisting of vaginal distension (VD) and pudendal nerve crush (PNC), results in slowed recovery of continence, as well as decreased expression of brain-derived neurotrophic factor (BDNF), a regenerative cytokine. Electrical stimulation has been shown to upregulate BDNF in motor neurons and facilitate axon regrowth through the increase of β(II)-tubulin expression after injury. In this study, female rats underwent selective pudendal nerve motor branch (PNMB) stimulation after simulated childbirth injury or sham injury to determine whether such stimulation affects bladder and anal function after injury and whether the stimulation increases BDNF expression in Onufs nucleus after injury. Rats received 4 h of VD followed by bilateral PNC and 1 h of subthreshold electrical stimulation of the left PNMB and sham stimulation of the right PNMB. Rats underwent filling cystometry and anal pressure recording before, during, and after the stimulation. Bladder and anal contractile function were partially disrupted after injury. PNMB stimulation temporarily inhibited bladder contraction after injury. Two days and 1 wk after injury, BDNF expression in Onufs nucleus of the stimulated side was significantly increased compared with the sham-stimulated side, whereas β(II)-tubulin expression in Onufs nucleus of the stimulated side was significantly increased only 1 wk after injury. Acute electrical stimulation of the pudendal nerve proximal to the crush site upregulates BDNF and β(II)-tubulin in Onufs nucleus after simulated childbirth injury, which could be a potential preventive option for SUI after childbirth injury.

Neurotrophin therapy improves recovery of the neuromuscular continence mechanism following simulated birth injury in rats

Stress urinary incontinence (SUI) affects women both acutely and chronically after vaginal delivery. Current SUI treatments assume the neuromuscular continence mechanism, comprised of the pudendal nerve (PN) and external urethral sphincter (EUS), is either intact or irreparable. This study investigated the ability of neurotrophin therapy to facilitate recovery of the neuromuscular continence mechanism.

Pudendal Nerve Stretch Reduces External Urethral Sphincter Activity in Rats

PURPOSE Most animal models of stress urinary incontinence simulate maternal injuries of childbirth since delivery is a major risk factor but they do not reproduce the nerve stretch known to occur during human childbirth. We hypothesized that pudendal nerve stretch produces reversible dysfunction of the external urethral sphincter. MATERIALS AND METHODS Female virgin Sprague-Dawley® rats were anesthetized with urethane. Bilateral pudendal nerve stretch or sham injury was performed for 5 minutes. External urethral sphincter electromyography and leak point pressure were recorded immediately before and after, and 10, 30, 60 and 120 minutes after pudendal nerve stretch. Post-pudendal nerve stretch results were compared to prestretch values and to values in sham injured animals. The pudendal nerves underwent qualitative histological assessment. The nucleus of Onuf was evaluated by immunohistochemistry and polymerase chain reaction for β-APP and c-Fos expression as markers of neuronal activity and injury. RESULTS A total of 14 rats underwent bilateral pudendal nerve stretch (9) or sham injury (5). Each nerve was stretched a mean ± SEM of 74% ± 18% on the left side and 63% ± 13% on the right side. Electromyography amplitude decreased significantly immediately after stretch compared to before stretch and after sham injury (p = 0.003) but it recovered by 30 minutes after stretch. There was no significant change in leak point pressure at any time. Two hours after injury histology showed occasional neuronal degeneration. β-APP and c-Fos expression was similar in the 2 groups. CONCLUSIONS Acute pudendal nerve stretch produces reversible electrophysiological dysfunction but without leak point pressure impairment. Pudendal nerve stretch shows promise in modeling injury. It should be tested as part of a multi-injury, chronic, physiological model of human childbirth injury.