The urethra serves a dual function by maintaining continence during bladder filling and aiding the release of urine during micturition. Within the urethra, a sphincter region containing both smooth and striated muscle layers normally prevents involuntary leakage of urine. However, patients with stress urinary incontinence lose this ability upon sudden increases in intravesical pressure (i.e. from coughing, straining, etc.). This condition has been associated with a decline in striated muscle, which may be susceptible to direct muscle or associated nerve damage. Cellular uromyoplasty proposes to augment this muscle layer through the transplantation of myogenic progenitors. The goal of this work was to address current deficiencies regarding the isolation and identification of efficient progenitors, and the urethral biomechanical consequences of striated muscle restoration. Both issues are essential for effective clinical implementation of this therapeutic approach.
The ability of various progenitor populations to regenerate skeletal (striated) muscle was assessed in a dystrophic mouse model. Both cell surface protein expression and behavioral characteristics were investigated for their potential use as indicators of regenerative efficiency. The results demonstrate the limited utility of surface proteins due to fluctuations in expression and lack of regenerative consistency between directly-isolated and cultured cell populations. Behavioral characteristics related to the ability of cells to maintain a proliferative phenotype under differentiation-inducing conditions appears more promising in this regard, and indicates that in vivo expansion of transplanted cells may be a critical variable in the regeneration process.
A new ex vivo method to assess the regional biomechanical function of the intact urethra, under physiologic loading conditions, was introduced and validated. Quantitative characterization and comparison of tissue responses to applied intralumenal pressures was performed in the presence or absence of selected muscle activity. The dominant smooth muscle influence observed suggests that a large degree of striated regeneration may be necessary to impart functional changes in urethra mechanics. Importantly, these results also indicate that muscle fiber orientation may significantly impact urethra closure function.
Together, this information will be useful in progressing uromyoplasty therapy toward clinical utility, and aid the broader scientific community investigating myogenic cell transplantation and lower urinary tract function.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04222003-124025 |
| Date | 12 November 2003 |
| Creators | Jankowski, Ronald Jay |
| Contributors | William Wagner, David Vorp, Michael Chancellor, Lars Gilbertson, Harvey Borovetz, Johnny Huard |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04222003-124025/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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