Stem Cells for Urinary Incontinence: Functional Differentiation or Cytokine Effects?

Minimally-invasive stem cell therapy for stress urinary incontinence may provide an effective nonsurgical treatment for this common condition. Clinical trials of periurethral stem cell injection have been underway and basic science research has demonstrated the efficacy of both local and systemic stem cell therapies. Results differ as to whether stem cells have a therapeutic effect by differentiating into permanent, functional tissues, or whether they exert benefits through a transient presence and the secretion of regenerative factors. This review explores the fate of therapeutic stem cells for stress urinary incontinence and how this may relate to their mechanism of action.

Introduction

Urinary incontinence afflicts up to 1 in 2 women.¹ It poses significant economic and quality of life burdens, with over $32 billion annual U.S. dollars spent managing it.² Stress urinary incontinence (SUI) impacts up to 1 in 4 women and accounts for over $12 billion annual U.S. dollars in health care costs.¹ Incontinence imparts major psychosocial burdens on those afflicted by it, and places women at risk for other debilitating conditions, including depression, anxiety, low self-esteem, social isolation, infection, pain, and sexual dysfunction.³ Therefore, a clear need to develop cost-effective, durable, and minimally invasive treatment for the condition exists.

Some patients with SUI effectively respond to conservative treatment, including pelvic floor physical therapy, biofeedback, pelvic floor electrical stimulation, or continence devices, such as pessaries.^4, 5 Several surgical and transurethral treatments are also available, including peri-urethral bulking injections and sub-urethral slings, which are the gold standard therapy for the condition.⁶ Slings offer the highest long-term cure rate for SUI, but like any surgery, are not without complications, which include sling erosion, urinary retention, bladder perforation, wound issues, and pain.⁷ Moreover, reports of complications involving vaginal mesh, while not pertaining to mid-urethral slings, have negatively swayed public opinion about such procedures.⁸ To date, besides conservative treatments, injectable therapies used to coapt the urethral lumen remain the least invasive SUI treatments providing some clinical benefit. These interventions produce no visible scars, but have largely fallen from clinical favor due to limited durability and efficacy.⁹

The utilization of stem cells and other progenitor cells as injectable agents, via a similar approach as bulking agents, present potential alternate therapies. Stem cells are unique due to their ability to proliferate, self-renew, and produce a population of differentiated progeny, making them a promising therapy in the field of regenerative medicine. To date, stem cells have been classified into four main categories. Embryonic stem cells (ESCs) derived from human blastocysts represent the most undifferentiated form, possessing the ability to differentiate into any human cell type.¹⁰ Theoretically, they provide the greatest therapeutic potential but their use is restricted by ethical concerns, as well as potential allogenicity and tumor oncogenesis.¹¹ Amniotic fluid-derived stem cells (AFSCs) are a second form. This heterogeneous cell population is isolated from the amniotic fluid or placental membrane of a developing fetus, but their proliferation potential is only intermediate along the stem cell spectrum. Like ESCs, AFSCs can differentiate into many different cell lineages, but they are felt to possess lower tumorigenicity.¹² A third form are differentiated, somatic cells that are “reprogrammed” into pluripotent cells.¹³ These induced pluripotent stem cells (IPSCs) possess similar differentiation potential to ESCs but preclude the necessity of an embryo. The utility of IPSCs in regenerative urology requires further investigation. Lastly, adult stem cells (ASCs) represent the most well understood type. These are tissue-specific progenitor cells, which are the most limited on the spectrum of differentiation.¹⁴ Mesenchymal stem cells (MSCs) are a subset of ASCs that can be isolated from bone marrow and induced to differentiate into various cell lineages. Recently, alternative sources of ASCs, such as muscle-derived stem cells (MDSCs) and adipose-derived stem cells (ADSCs) have been obtained with less invasive techniques compared to MSCs.¹⁵

In the pre-clinical setting, a variety of SUI models exist for investigating pathophysiology and treatment.^19, 20 Leak point pressure (LPP), a measure of urethral resistance to leakage, determined by measuring bladder pressure at the time of leak, is a frequently utilized surrogate for SUI. Methods to decrease urethral resistance in order to elicit SUI are numerous and include direct urethral injury, urethrolysis, pudendal nerve injury, and vaginal distension.^21–26 Bladder pressure can be increased to induce leakage using direct bladder compression, sneeze testing, or direct infusion using a suprapubic catheter.^26–28 Additional assessments of these models include measurement of urethral closure pressure, testing of EUS function via electromyography (EMG), and histological studies of the EUS investigating muscle content and organization.¹⁹

This review addresses various applications of stem cells and progenitor cells to SUI, with a focus on recent developments in the field. The article also gives specific consideration to the mechanisms of therapeutic benefit from such cells, as well as implications for future studies and clinical applications. Commentary on the economic aspects of regenerative therapy for SUI is also included.

For the entire article / clinical trial, please click on the link below:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345159/