Stress urinary incontinence (SUI) is a devastating condition affecting millions of American women. For these patients urinary incontinence is not only an embarrassing condition significantly eroding quality of life, it is also a significant cause of hospitalization. In 1995 the annual cost of incontinence in the United States was estimated to be 26.3 billion dollars. It affects women of reproductive age who are at risk after vaginal deliveries. Its incidence increases with advancing age, making it a major quality of life issue for the elderly. Developing a minimally invasive procedure with high and durable cure rates would have a significant impact on the way physicians treat incontinence and a positive financial impact on health care expenditures. More importantly, it will dramatically improve the quality of life of these patients. With aging there is atrophy of the smooth musculature of the urethra contributing to poor urethral resistance and involuntary loss of urine. Bioengineering new functional tissue in order to increase urethral resistance and improve function has enormous clinical potential for the treatment of stress urinary incontinence. The long-term objective of this application is to apply tissue-engineering techniques exploiting the properties of adult stem cells derived from adipose tissue to develop an effective, minimally invasive treatment for stress incontinence. Our central hypothesis is that human adipose tissue contains a population of pluripotent stem cells capable of differentiating into functional smooth muscle. Specifically, this proposal aims at developing an injectable combination of cells, factors, and matrix to promote the development of vascularized, longlasting functional urethral musculature.
The specific aims of this application are: (1) to investigate the ability of human adipose derived stem cells to form functional smooth muscle, (2) to investigate the ability of human adipose derived stem cells to be delivered, survive, and function as normal smooth musculature in the lower urinary tract, (3) to determine the ability of these cells to repair the atrophic nonfunctional urethra of stress incontinence. We will accomplish these aims by evaluating the ability of clonal populations of adipose derived stem cells to differentiate phenotypically and functionally into smooth muscle. Lastly, we will use an animal model of incontinence and decreased urethral resistance to test the hypothesis that these cells can be used to reconstruct a functional urethra as a treatment of stress incontinence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067198-04
Application #
7221950
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Kusek, John W
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$344,262
Indirect Cost
Name
University of California Los Angeles
Department
Urology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Zhang, Rong; Jack, Gregory S; Rao, Nagesh et al. (2012) Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment. Stem Cells 30:481-90
Jack, Gregory S; Zhang, Rong; Lee, Min et al. (2009) Urinary bladder smooth muscle engineered from adipose stem cells and a three dimensional synthetic composite. Biomaterials 30:3259-70
Rodriguez, Larissa V; Alfonso, Zeni; Zhang, Rong et al. (2006) Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells. Proc Natl Acad Sci U S A 103:12167-72
Jack, Gregory S; Almeida, Fernando G; Zhang, Rong et al. (2005) Processed lipoaspirate cells for tissue engineering of the lower urinary tract: implications for the treatment of stress urinary incontinence and bladder reconstruction. J Urol 174:2041-5
Rodriguez, Larissa V; Chen, Shinhong; Jack, Gregory S et al. (2005) New objective measures to quantify stress urinary incontinence in a novel durable animal model of intrinsic sphincter deficiency. Am J Physiol Regul Integr Comp Physiol 288:R1332-8