Stress urinary incontinence (SUI) severely affects the quality of life of up to 13 million people in the USA. Its pathological processes include dysfunctional sphincter muscle tissue, chronic nerve injury, and poor regional blood supply. Some current therapeutic approaches are pharmacotherapy, sling surgery, and injection of bulking agents. Cellular-based therapy is a promising alternative method to restore deficient urethral sphincter function in the treatment of SUI. We have demonstrated that adult stem cells exist in human urine. These cells, termed urine-derived stem cells (USCs), possess stem cell characteristics with robust proliferative potential and multi-potential differentiation. These cell can be obtained using simple, safe, non-invasive and low-cost procedures, thus avoiding the adverse events associated with obtaining stem cells from other sources. Improving the urethral sphincter microenvironment by angiogenesis is critical for success of stem cell therapy determined by cell survival, ingrowth and differentiation, and host cell recruitment to aid urethra sphincter tissue repair. It is desirable to employ a safer approach to growth factor delivery to enhance the stem cell niches (microenvironment). Insulin-like growth factor 1 (IGF-1) promotes myogenesis and induces nerve regeneration after injury, and it also stimulates angiogenesis. Our recent studies demonstrated that USCs secreted high levels of IGF1 and IGF binding protein 1, and implanted USCs significantly enhanced sphincter function after vaginal distention in vivo. Moreover, we demonstrated that an alginate microbead delivery system is feasible to control growth factor release and thereby enhance survival and differentiation of grafted stem cells in vivo. Thus, the ultimate goal of this project is to develop a therapeutic approach to improve the outcomes of stem cell therapy and eventually lead to treatments and possibly cures for urinary incontinence. To do so, we will develop coherent experimental protocols to study a combination of stem cells and growth factor delivery to enhance angiogenesis and promote cell survival, growth, myogenic differentiation, and innervation in vivo. We hypothesize that IGF1 released from alginate microbeads can improve cell survival, enhance ingrowth and differentiation of USCs, and recruit resident cells to take part in urethral sphincter tissue repai via Akt-mediated signaling pathways. To test these hypotheses, we propose the following Specific Aims:
Aim 1. Elucidate the mechanisms by which USCs improve sphincter tissue repair in an athymic rat model of SUI.
Aim 2. Determine the effects of controlled release of IGF1 from alginate microbeads on sphincter tissue repair in vivo.
Aim 3. Determine the impact of USCs and IGF1 in combination on urethral sphincter regeneration after vaginal distention. The systematic approach will provide us with a critical tool to investigate how to manipulate biological interactions between stem cells and IGF1 that impair urethral tissue regeneration. Successful completion of this project will develop a therapeutic strategy for clinical trials of autologous USCs for urinary incontinence.
Currently, patients with stress urinary incontinence are treated surgically or with cell therapy;but either approach is invasive and carries risk of complications, and cost is considerable for the estimated 13 million Americans with this disorder. This proposal describes a novel technique, using stem cells derived from the patient's own urine grown on a customized biomaterial, and combined with growth factor slowly released from microbeads to enhance urethral sphincter muscle tissue regeneration, microvessel formation, and nerve tissue repair. This approach holds potential as an improved treatment for serious urethral sphincter disorders.
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