The concept of regenerating damaged tissue using selective cell transplantation has been applied clinically for a variety of muscle disorders, including stress urinary incontinence (SUI), which is a manifestation of several kinds of injuries and congenital abnormalities leading to sphincteric muscle deficiency (SMD). Results of recent clinical trials using autologous muscle-derived progenitor cells (MPCs) to treat SMD in women are promising. However, it remains unclear whether injected MPCs play a passive (bulking), or active (cell integration) role in sphincter regeneration and recent concern has been raised about the short- and long-term success rates of these clinical trials. Repeated clinical trials will take time and still lack a mechanistic explanation for their results. We propose to address these two issues in a study designed to evaluate the role of MPCs as active participants in restoration of reflex control over micturition using a cynomolgus monkey (Cyno) model of injury- induced SMD, where measures of success can be achieved in relatively few years. Two findings from our lab (one in rats and one in dogs) support the working hypothesis that injected MPCs integrate and play an active role in sphincter regeneration of females. Based on the current uncertainties associated with this therapeutic approach and the need for results that are more directly translatable to human beings, we propose to extend our studies to adult female Cyno's - at the age equivalent of 45-50 year-old women - whose genetic, anatomic, physiologic, postural, intra-pelvic bladder location, age and hormone-related changes in the genitourinary system, expose the urinary sphincter to structural and pharmacologic stressors common to middle-aged women.
The specific aims are: 1. To establish a Cyno model of injury-induced SMD. This will be achieved by applying our canine model of sphincter muscle removal to adult female Cyno's and then measuring longitudinal changes in urinary sphincter structure (histological and molecular analysis of engraftment characteristics such as: sphincter content of labeled cells, injected cell viability, formation of functional motor endplates and gene expression data) and function (resting and reflex urodynamics, responses to pharmacologic and electric field stimulation) at 3mo., 6mo., 12mo., and 24 mo. post injury ( this will be equivalent to a 6 year follow-up study in human beings);and 2. To measure the effects of MPC cell therapy in the Cyno model of injury-induced SMD. First, we will optimize the culture system to produce sufficient numbers of functional lenti-LacZ transfected Cyno-derived MPCs for use in the treatment of SMD and then inject the labeled MPCs into the damaged sphincter muscle and then measure the longitudinal (same time- points as SA1) effects of these cells on sphincter function and structure. It is anticipated that the results obtained from this primate model will be directly translatable to women of this age-group, to other patients with SMD and to regeneration of other muscle tissues and muscle cell-based bioengineered organs.
An unanswered question about cell therapy for sphincter muscle deficiency (SMD) -associated stress urinary incontinence is whether the injected cells play a passive, or an active role in clinical improvement. The proposed studies will utilize adult female nonhuman primates to measure the longitudinal effects of muscle progenitor cells on both structural and functional changes in an injury model of SMD. We anticipate that longitudinal and parallel assessments of structure (MPC viability, functionality, and contribution to motor endplate formation) and function (resting and reflex urodynamic measures) will help determine the role (active or passive) of MPC cell therapy in restoration of a functional sphincter.
|Williams, J Koudy; Badlani, Gopal; Dean, Ashley et al. (2016) Local versus intravenous injections of skeletal muscle precursor cells in nonhuman primates with acute or chronic intrinsic urinary sphincter deficiency. Stem Cell Res Ther 7:147|
|Badra, Sherif; Andersson, Karl-Erik; Dean, Ashley et al. (2013) Long-term structural and functional effects of autologous muscle precursor cell therapy in a nonhuman primate model of urinary sphincter deficiency. J Urol 190:1938-45|