Stem Cell Therapy for Chronic Bladder Ischemia

Introduction

Among various problems associated with voiding dysfunction, stress urinary incontinence (SUI) and overactive bladder (OAB) are two of the challenges urologists face. Stem cell therapy shows a promising future in treating lower urinary tract dysfunction, erectile dysfunction, bladder trauma, and renal disease. Stem cells have a role in multilineage differentiation and self-renewal, which helps in tissue repair and regeneration. In addition, stem cells secrete bioactive factors such as anti-scarring, neovascularization, and antiapoptotic and immunomodulatory effects and direct the cells (progenitor and stem cells) to the site of injury.

What Are the Clinical Problems Associated With Urinary Incontinence?

Stress Urinary Incontinence in Women:

Involuntary leakage of urine due to the absence of bladder contraction resulting due to increased abdominal pressure. This happens when there is a failure of the pelvic floor muscles, urethral sphincter, and fascial tissues to provide closure. When Intra abdominal pressure exceeds urethral pressure, it leads to SUI. Incidence is higher in older women than compared in younger women. Urethral pressure depends on factors such as urethral sphincter musculature, bladder neck position, sphincter innervation, and vascular supply.

Pregnancy and Childbirth Are Risk Factors That May Cause Injuries Such as :

1. Vascular damage due to fetal compression of pelvic structures.

2. Injury to connective tissue during vaginal birth.

3. Traumatic injury to pelvic muscles and nerves.

4. Injury to the lower urinary tract during childbirth.

Treatment involves conservative approaches such as biofeedback, electrical stimulation, pelvic floor physiotherapy, and sometimes pharmacotherapy. Surgical modalities involve urethral slings and suspensions, artificial urethral sphincters, transurethral bulking agents, and bulbar urethral slings.

Stress Urinary Incontinence in Men :

Radical prostatectomy is one of the major causes of SUI in men. Post prostatectomy results from failure to store urine which is further caused by inadequate resistance of the outlet sphincter.

Overactive Bladder:

Around 12 % of men and women are affected by an overactive bladder. With increasing age, overactive bladder without urgency incontinence is common among older men, and OAB with urgency is common in females. Signs and symptoms include urgency, with or without urgency, incontinence, frequency, and nocturia. Treatment options involve pharmacological interventions such as anticholinergic drugs and beta-3 adrenergic. Non-pharmacological options involve biofeedback, behavioral and dietary modifications, and sacral neuromodulation.

What Are the Sources of Stem Cells?

Stem cells are divided into the following categories:

1. Stem Cells Are Derived From Early-Stage Embryos (ESCs): They contain all adult cell types and are a pluripotent cell source, and have great therapeutic potential.

2. Derived From the Placenta or Amniotic Fluid (AFPS): They are heterogeneous stem cell populations obtained from amniotic fluid and placental membrane, and they contain mesenchymal cells and multipotent AFPS that have renewal capacity. AFPS cells can be differentiated into all three germ layers, which include cells of osteogenic, myogenic, endothelial, adipogenic, hepatic, and neural lineages.

3. Induced Pluripotent Stem Cells (IPSC): Have potency of multipotent differentiation and self-renewal. The disadvantages involve the time required in setting the cells in the pluripotent stage and also the time required to differentiate them into the desired lineage.

4. Adult Stem Cells (ACS): These cells have been used in urologic applications. They help in acting on tissue-specific progenitors, which help in repairing damage and restoring functions. Multipotent adult progenitor cells (MCS) are a subset of adult stem cells which is obtained from bone marrow stroma and vascularized tissues such as the endometrium, kidney, adipose, and muscle.

5. Urine-Derived Stem Cells (USC): These cells have potential in urologic applications and can be isolated from voided urine. They show features of multipotent differentiation, self-renewal, and clonogenicity. It can differentiate in multicell lineages at the cellular, gene protein expression, and tissue levels. Holds advantages in urinary incontinence and voiding dysfunction as a cell source.

What Is the Mechanism of Action of Stem Cells?

Stem Cell Homing:

The delivery of stem cells to the site of injury is called homing. The progenitor cells, along with multipotent adult progenitor cells, enter the systemic circulation and reach areas of acute injury along with chemokine gradients which help in regeneration and healing. The homing of stem cells depends on the leukocytic migration to hematopoietic stem cells, metastatic cancer cells, and injured tissue. The MSCs also help in cellular migration and homing by chemoattraction, adhesion to vascular endothelial cells, and transmigration across the endothelium to the site of injury. Integrins and selections help in the direction of migration and adhesion of cells, including the MSCs.

Stem Cell Differentiation:

Stem cell differentiation is one of the major factors considered for the treatment of various urological dysfunctions, such as voiding dysfunction and urinary incontinence. For example, in stress urinary incontinence, the MSCs restore function mainly by their ability to differentiate into multiple cell lineages and also play a major role in the regeneration process.

How Is Stem Cell Therapy Used for Voiding Dysfunction?

Stem Cells for Stress Urinary Continence:

Voiding dysfunction causes damage to the surrounding muscles and nerves responsible for urinary incontinence. Several studies have been conducted to analyze the mechanism of injury to the continence mechanism; they include:

1. Stimulation of nerve injury by pudendal nerve crush (PNC).

2. Stimulation of anatomic nerve support with pubourethral ligament injury or urethrolysis.

3. Stimulation of intrinsic urethral defects with periurethral cauterization, urethral sphincterotomy, or pudendal nerve transection.

4. Combination of both voiding dysfunction and pudendal nerve crush.

In studies conducted on animals, medals show the efficacy of MSCs and ADSCs for mechanical, nerve, or external urethral sphincter injury. For example, in a study conducted by Kim et al., MDSCs were injected into the urethra of rats that had pudendal nerve dissection. Four weeks after the MDSCs, the urethral closure pressure was restored, and the injected MDSCs stained positive for muscle-specific markers, which helped in the repair of damaged muscle tissue.

Stem Cells for Overactive Bladder:

In a study conducted by Lee et al., 2012 MSCs with nanoparticles were injected into the bladder wall of rats following partial bladder outlet obstruction. It was followed up by histology, magnetic resonance imaging, and functional tests. It increased TGF-β protein and collagen factors. The study concluded that MSCs restore bladder function in rats with bladder outlet obstruction.

Conclusion

Stem cell therapy shows a promising future in urological complications such as voiding dysfunction and urinary incontinence. Applications have shown a success rate in animal clinical trials. With limited treatment to urological complications, its approach towards it through cell regeneration and differentiation will help in a better prognosis.