Stem Cell Homing for Treatment of Female Pelvic Floor Disorders

Summary

Principal Investigator: Margot S Damaser
Abstract: DESCRIPTION (provided by applicant): Up to half the women in the U.S. experience female pelvic floor disorders (FPFD): stress urinary incontinence (SUI), fecal incontinence, and pelvic organ prolapse (POP). These conditions share common risk factors, including vaginal delivery, and therefore ought to be studied together. The lifetime risk of surgery for FPFD is 11%, with a re-operation rate of 29%. Since age, diabetes, and obesity are risk factors for FPFD, the aging US population and increasing prevalence of obesity and diabetes portend an FPFD epidemic in the U.S. in the coming decades. Female reproductive organs and the pelvic floor are rich in elastic fibers and undergo massive remodeling during pregnancy and childbirth. Lysyl oxidase-like 1 (LOXL1) is a protein essential for elastin remodeling and homeostasis. Unlike in normal mice, vaginal delivery in LOXL1 knockout (KO) mice results in POP and SUI, making it an ideal animal model of FPFD. Stem cells participate in normal repair processes and have the potential to be harnessed as a preventative therapy to facilitate repair after childbirth. We have preliminary data demonstrating that stem cells increase the elastin content of lower urinary tract tissues, suggesting the feasibility of stem cell administration to facilitate recovery after delivery and prevent FPFD. Cytokine gradients produced by injured tissues attract or home circulating stem cells to sites of injury, where they facilitate repair. Since the injuries that cause FPFD are too diffuse to be amenable to direct stem cell injection therapy, stem cell homing could be utilized to provide a viable therapy to facilitate repair after delivery and prevent FPFD. Recent research has demonstrated that stem cells can facilitate repair after injury by secreting paracrine-acting proteins such as growth factors. Identification of these factors may provide a viable noncellular therapy to facilitate repair after childbirth and prevent FPFD. We will utilize the LOXL1 KO mouse model to study if a cellular or noncellular stem cell-based reparative therapy could be utilized to prevent FPFD. The hypothesis to be tested in this project is that mesenchymal stem cells home to pelvic organs after delivery, facilitate recovery, and prevent resultant FPFD via secretion of paracrine factors. This hypothesis will be tested with the following Specific Aims: SA1. Determine the time course over which cytokines involved in stem cell homing and tissue repair are upregulated by the genitourinary organs after vaginal delivery or C-section delivery in LOXL1 KO mice. We will screen for upregulation of potential stem cell homing cytokines with a chemokine/chemokine receptor array system. Confirmation and localization will be made using RT-PCR and immunohistochemistry. SA2. Optimize the dose and timing of MSCs to best facilitate recovery from the maternal pelvic injuries of delivery and prevent FPFD. Fluorescently labeled MSCs will be infused at several time points after pup delivery in female LOXL1 KO mice. Outcomes will include staging of POP, urodynamics, quantitative histological morphometry assessment of elastin amount and pattern of clustering in genitourinary organs. SA3. Determine the receptor-mediated mechanisms of MSC homing &accelerated functional recovery from vaginal delivery. Female LOXL1 KO mice will undergo vaginal delivery and will receive an infusion of MSCs in which homing cytokine receptors have been knocked down via transfection with small interfering RNA (siRNA). The dose and time point of MSC infusion after vaginal delivery identified as most effective in SA2 will be used for the experiments of SA3. Outcomes of SA3 will be the same as in SA2. SA4. Determine the noncellular mechanisms of accelerated functional recovery from vaginal delivery. Infusion of MSCs will be compared to injection of concentrated conditioned media (CCM) from these stem cells. We will utilize both MSCs and CCM of MSCs generated from wild type and LOXL1 KO mice. We will also use siRNA to knock down secreted paracrine factors in MSCs and utilize both the MSCs and CCM from these cells. The dose and time point of MSC infusion after vaginal delivery identified as most effective in SA2 will be used for the experiments of SA4. Outcomes of SA4 will be the same as in SA2 &SA3. Significance. The maternal injuries of childbirth are diffuse and involve injury to many small structures, such as pelvic floor fascia as well as pelvic organs, making direct injection stem cell therapy to all these sites impossible. Therefore, therapies based on stem cell homing or on the systemic effects of stem cells may provide a viable method to facilitate repair of injured tissues and prevent FPFD. In addition, identification of the paracrine factors produced by stem cells and introduction of these factors after delivery may provide a viable noncellular reparative therapy to prevent FPFD. Thus, this research is highly innovative and is of high significance for FPFD. PUBLIC HEALTH RELEVANCE: Up to half the women in the U.S. experience female pelvic floor disorders: stress urinary incontinence, fecal incontinence, and pelvic organ prolapse, but little is known about their pathophysiology and few nonsurgical treatments are available. In this project, we will use an animal model to determine if homing of adult mesenchymal stem cells could provide a possible nonsurgical treatment or preventative option. We will explore the possibility of making this therapy noncellular to avoid complications of cell therapy. This research is of high significance for development of improved therapies for female pelvic floor disorders.
Funding Period: 2010-08-16 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Stem cell therapy for incontinence: where are we now? What is the realistic potential?
    Charuspong Dissaranan
    Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Curr Urol Rep 12:336-44. 2011
  2. pmc Pelvic organ distribution of mesenchymal stem cells injected intravenously after simulated childbirth injury in female rats
    Michelle Cruz
    Department of Biomedical Engineering, The Cleveland Clinic, Euclid Avenu ND20, Cleveland, OH 44195, USA
    Obstet Gynecol Int 2012:612946. 2012
  3. pmc Will we ever use stem cells for the treatment of SUI? ICI-RS 2011
    Howard B Goldman
    Section of Female Pelvic Medicine and Reconstructive Surgery, Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
    Neurourol Urodyn 31:386-9. 2012

Detail Information

Publications5

  1. pmc Stem cell therapy for incontinence: where are we now? What is the realistic potential?
    Charuspong Dissaranan
    Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Curr Urol Rep 12:336-44. 2011
    ..This article reviews the progress in stem cell research for incontinence and describes areas of future work as suggested by research in other fields...
  2. pmc Pelvic organ distribution of mesenchymal stem cells injected intravenously after simulated childbirth injury in female rats
    Michelle Cruz
    Department of Biomedical Engineering, The Cleveland Clinic, Euclid Avenu ND20, Cleveland, OH 44195, USA
    Obstet Gynecol Int 2012:612946. 2012
    ..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...
  3. pmc Will we ever use stem cells for the treatment of SUI? ICI-RS 2011
    Howard B Goldman
    Section of Female Pelvic Medicine and Reconstructive Surgery, Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
    Neurourol Urodyn 31:386-9. 2012
    ..To review the current state of research in the use of stem cells (SCs) for stress urinary incontinence (SUI) and assess the likelihood of this becoming a relevant treatment option...

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  3. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  4. Tissue recovery in the pathophysiology of stress urinary incontinence
    Adonis K Hijaz; Fiscal Year: 2013
    ....
  5. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  6. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  7. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  8. Mechanisms/Treatments of Lower Urinary Tract Dysfunction After Spinal Cord Injury
    ANTHONY JOHN KANAI; Fiscal Year: 2013
    ..We are confident that our experience and unique approaches will lead to a very interactive and fruitful program. ..
  9. PDE5A Inhibition Stimulates Stem Cell Survival &Differentiation
    Muhammad Ashraf; Fiscal Year: 2013
    ..The proposed study using the PDE5A inhibitors may identify a potential therapeutic role for these compounds for stem cell based de novo myocardial regeneration. ..
  10. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  11. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  12. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  13. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  14. Engineered Induction of a Stem Cell Homing Response
    JEFFREY MICHAEL KARP; Fiscal Year: 2013
    ....