Jankowski, Ronald Jay
(2003)
Development of a muscle progenitor cell-based therapeutic approach for the treatment of stress urinary incontinence.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
12 November 2003 |
| Date Type: |
Completion |
| Defense Date: |
17 April 2003 |
| Approval Date: |
12 November 2003 |
| Submission Date: |
22 April 2003 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
biomechanics; flow cytometry; incontinence; isolation; progenitors; regeneration; smooth muscle; striated muscle; transplantation; urethra |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04222003-124025/, etd-04222003-124025 |
| Date Deposited: |
10 Nov 2011 19:40 |
| Last Modified: |
15 Nov 2016 13:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/7475 |
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