Mesenchymal Stem cells for the treatment of stress urinary incontinence, what have we learned.
Up to half of all women over the age of 40 experience stress urinary incontinence (SUI)- the involuntary leakage of urine on effort or exertion, or on sneezing or coughing- including approximately 25 million Americans overall. These numbers are expected to increase at least 2- to 3-fold within the next 20 years based on extrapolation from the 2000 US Census data.
Stem cell therapy and tissue engineering are among the newest strategies under investigation for the treatment and prevention of SUI. A number of animal studies have been applied mesenchymal stem cells (MSCs) to improve SUI in animal models of urinary incontinence. These studies showed that local application of MSCs in an animal model of SUI restored the damaged external urethral sphincter and significantly improved SUI. It is important to note that all of these studies involved either local or systemic injections of MSCs at the time of injury. Recently Williams et al, reported outcomes of combined skeletal myoblasts and CXCL12 (SDF-1) injection in rat model of intrinsic sphincter deficiency (ISD) and non-human primate model of chronic ISD. The therapy was done 30 days after ISD induction in the rat model and 6 months after ISD (retropubic urethrolysis and pudendal nerve injury) in the nonhuman primate model. In both the skeletal myoblast alone were not effective in restoring continence as measured with LPP but the combination was effective. This is highly relevant in regards to clinical applications of MSCs as a therapy for treatment of SUI. Since at this time clinicians cannot preemptively predict which patient will develop SUI, it is likely that MSCs will be used in a “cold environment” remote from the time of injury. Thus, identifying mechanisms by which injury activates and retains MSCs will provide insights into development of therapies that may be used at a time remote from injury.
The first clinical series in the medical literature is with the use of muscle-derived cellular therapy by Carr et al from Canada. After approximately 17 months of follow-up, five patients out of eight remained in the study and had some improvement during follow-up, while one subject achieved total continence. The improvement in these subjects occurred between 3 and 8 months after the first injection. During follow-up, no serious adverse events were reported. In a recent phase I/II multicenter study using skeletal muscle-derived stem cell therapy in 80 patients with SUI, Peters et al reported 12-month safety and outcome data across a range of doses (10-200 × 106 cells). Only the 24 patients who received the highest dose had a statistically significant reduction in mean pad weight at 12 months, and at least a 50% reduction in stress leaks. Several additional clinical studies have been done evaluating SUI improvement after local injection of muscle derived stem cells and adipose derived stem cells (ADSCs) into the urethra.
Although most researchers investigating the pathophysiology of SUI have focused their efforts on evaluating the process of injury and its effect on the continence status, I propose that the clinical development of SUI following birth trauma is intimately related to an imbalance of injury and recovery processes. Epidemiologically, it has been demonstrated that women who do not recover continence function after birth trauma are at a higher risk of having SUI at 5 years following delivery. Thus, the focus of our research over the past several years has focused on the development of pathophysiologically based interventions for the treatment of SUI with an emphasis on MSC mediated recovery. Our recently published study demonstrated the efficacy of hMSCs to restore continence in a rat model of birth-trauma injury. Our overarching aim is to harness this knowledge to develop products that can independently or synergistically be used with MSCs in the treatment of SUI at a time remote from that of injury.