Stem Cell Homing for Stress Urinary Incontinence

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Prevalence data suggest that during their lifetimes, up to half of U.S. women experience some level of female pelvic floor disorders (FPFD). However, despite the prevalence of FPFD, little is known about their pathophysiology.

Development of FPFD later in life is strongly linked to vaginal delivery of children. Longer duration of second-stage labor, greater fetal weight, and older age of the mother all increase the risk of developing FPFD, particularly stress urinary incontinence (SUI). We have been working with several animal models of FPFD and have developed a method of simulating childbirth injuries in rodents via a vaginal distension procedure.

We also have developed a method of determining the competence of the continence mechanism in these animals, using a version of leak point pressure (LPP) measurement adapted for animals. In the animals, recovery depends on duration of distension: the longer the duration of distension, the longer the time to recovery.

There is, therefore, a healing and recovery mechanism that occurs endogenously in the animals. If this molecular mechanism could be exploited and applied clinically, it could be used to accelerate recovery from childbirth injuries and potentially treat or prevent SUI and FPFD.

Findings after cardiac infarction suggest that injury triggers the transient overexpression of homing cytokines, which mobilize the animal's own bone marrow stem cells to migrate or “home” to the area of injury for repair, resulting in improved cardiac function.

We hypothesized that the recovery of continence after vaginal distension may be a result of expression of these homing molecules and subsequent migration of stem cells to the injured area. In our laboratories, we have determined that one of these homing molecules (MCP-3) is strongly overexpressed in the urethra and vagina after vaginal distension, but the other (SDF-1) is not.

Likewise, one of the receptors for MCP-3 (CCR1) is overexpressed but the receptor for SDF-1 (CXCR4) is not, further confirming that MCP-3 is likely the active homing agent involved in recovery from this simulated childbirth injury.

We recently have infused bone marrow stem cells IV after vaginal distension to test the hypothesis that they will home to injured tissues and enhance recovery of urethral funchave demonstrated that animals who received stem cells recovered normal urethral function, as measured by LPP, more quickly than animals who received only saline. Thus, IV infusion of stem cells may provide a mechanism to facilitate healing after an injury such as might be sustained during vaginal delivery.

Alternatively, injection of homing molecules could be used to attract a patient's own bone marrow stem cells to the site of injury and facilitate the natural healing response to injury. Preclinical testing of these two possible therapies will help us better understand the mechanism of injury and recovery in the lower urinary tract after vaginal delivery and provide a potentially new medical intervention using stem-cell recruitment as a treatment modality for SUI and other FPFD.

Adonis Hijaz, MD, Lynn Woo, MD, Hadley Wood, MD, Raymond R.Rackley, MD, and Marc Penn, MD PhD, also contributed to this article.

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