Stress urinary incontinence (SUI) affects approximately 35% of women over the age of 40 and carries a large social, medical and personal burden. Development of SUI is strongly associated with pregnancy, vaginal delivery and aging. Vaginal delivery results in injury to the pelvic floor and continence mechanism;however, injury alone does not explain the entire picture on the pathophysiological mechanisms of SUI. Clinical and experimental data suggest that recovery from the injury or lack thereof, following childbirth trauma is as significant to the pathophysiology of SUI. Approximately 1/3 of women develop SUI following delivery but in most women this resolves within a year. Impaired recovery significantly increases the chance of recurrence of SUI over time. Understanding the mechanisms mediating the balance between injury and recovery appear to be the key in understanding the role of promoting factors such as diabetes or obesity, and decompensating factors such as aging in the pathophysiology of SUI. We, and other investigators, have used animal models to investigate the mechanisms of SUI. These investigations have shown that a) vaginal distension (VD) models of SUI simulate the birth related trauma to the pelvic organs similar to the passage of the fetal head through the birth canal in women as an acute reversible model of injury;b) decompensating factors such as diabetes mellitus causes both increased severity (injury) and delayed recovery from VD induced SUI;c) following VD, expression of monocyte chemotactic protein-3 (MCP-3)- a mesenchymal stem cell (MSC) homing cytokine- is dramatically increased in the urethra;and d) selective homing of intravenously infused MSCs to the urethra following VD is associated with an accelerated functional recovery of the urethra. In several recent epidemiological studies, advanced maternal age has been reported as a plausible risk factor for development of SUI following birth trauma. These observations have MAJOR clinical and social implications as they propose to answer the question of whether risk of development of SUI following vaginal delivery justifies the recommendation for primary elective C-section, especially in mothers who are older than age of 30 with their 1st pregnancy. Thus, in this application I hypothesize that the development of SUI is the result of im/balance between two interacting processes: 1)Injury- from child birth related trauma to the tissues of the lower urinary tract and pelvic floor and 2)Recovery- ability of the injured tissues to recover from birth trauma injury. I further hypothesize that recovery is intimately related to the mobilization of stem cells secondary to local expression of homing factors in the urethra following injury. I will investigate the impact of aging on this pathway. Aging model is chosen as a model for 'impaired recovery'. To test these hypotheses, I plan to carry out 2 lines of experiments: 1) to determine differential recovery patterns from injury in young fertile, old fertile and aged mice as measured by functional leak point pressure(LPP), morphometric outcomes and expression of paracrine factors in the micro environment of the continence mechanisms (urethra);2) to examine the therapeutic impact of intravenously injected human mesenchymal stem cells (hMSCs) in recovery of VD- induced SUI in the same group of mice using similar outcome measures. This mechanism is a very exciting mechanism as it provides us and the scientific community with imminently applicable therapeutic options.

Public Health Relevance

Stress Urinary Incontinence (SUI) presents a large social, medical and personal burden. Development of SUI is strongly associated with pregnancy, maternal age, vaginal delivery and aging. This study is directed at understanding the mechanisms mediating the balance between injury and recovery and the role of mesenchymal stem cells in recovery and to evaluate the effect of aging on the balance and response to stem cell therapy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZDK1-GRB-G (O2))
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Rankin, Tracy L
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Case Western Reserve University
Schools of Medicine
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Sadeghi, Zhina; Isariyawongse, Justin; Kavran, Michael et al. (2016) Mesenchymal stem cell therapy in a rat model of birth-trauma injury: functional improvements and biodistribution. Int Urogynecol J 27:291-300
Rivera-Delgado, Edgardo; Sadeghi, Zhina; Wang, Nick X et al. (2016) Local release from affinity-based polymers increases urethral concentration of the stem cell chemokine CCL7 in rats. Biomed Mater 11:025022
Cheng, Julie W; Sadeghi, Zhina; Levine, Alan D et al. (2014) The role of CXCL12 and CCL7 chemokines in immune regulation, embryonic development, and tissue regeneration. Cytokine 69:277-83
Hijaz, Adonis K; Grimberg, Kerry O; Tao, Mingfang et al. (2013) Stem cell homing factor, CCL7, expression in mouse models of stress urinary incontinence. Female Pelvic Med Reconstr Surg 19:356-61
Vricella, Gino J; Tao, Mingfang; Altuntas, Cengiz Z et al. (2010) Expression of monocyte chemotactic protein 3 following simulated birth trauma in a murine model of obesity. Urology 76:1517.e12-7