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Bladder: Major Pathologies

Bladder pathologies often involve injury and dysfunction of the smooth muscle of the bladder as well as its nerve supply. Stem cell therapy for bladder pathology is directed toward regeneration of functional muscle and nerves to restore bladder function. There are also treatments using stem cells that take advantage of other specific properties that stem cells possess. Currently, many alternative treatments exist for these bladder pathologies, but, the goal of stem cell therapy research is to reduce the adverse effects of treatment and to reduce cost. Many of the pathologies described below have suboptimal treatments. Without treating the conditions described, one risks complications, such as urinary tract infections or loss of urinary continence.

Stem cells begin by migrating to the injured tissue, such as the bladder. This migration is directed by the release of cytokines from the damaged tissue. Next, the stem cells differentiate into the specific tissue needed, such as smooth muscle and neural tissue. Finally, there is the paracrine effect, in which stem cells release certain factors that induce tissue regeneration and modulate inflammatory responses to injury in the original tissue. Through these mechanisms, stem cells can lead to regeneration and growth of injured tissue and restoration of function of damaged organs.

Stress Urinary Incontinence

Stress incontinence is a common medical condition that affects over 200 million people in the world. It is defined as involuntary leakage of urine with exertive actions such as coughing or sneezing that increase intra-abdominal pressure. This happens when the muscular internal or external sphincter of the bladder outlet tract, their blood supply, or their nerve supply are damaged. Current studies are comparing the use of mesenchymal and embryonic stem cells in the treatment of stress urinary incontinence versus the traditional surgical treatment. While the use of embryonic stem cells is still ethically controversial, mesenchymal stem cells from adult sources are currently being utilized. These mesenchymal stem cells can come from skeletal muscle, adipose tissue, or bone marrow. These stem cells can differentiate into a variety of tissue types and are classified as multipotent stem cells. The idea behind the use of stem cells is to regrow urethral sphincter muscle and nerve tissue by implanting the stem cells directly into the area and releasing certain factors that induce differentiation of the stem cells into the desired tissue type. These factors include basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), neuregulin, and forskolin. From the current studies that have been done, the use of stem cells in treating stress urinary incontinence has demonstrated good short-term outcomes in both clinical improvement and cure rate of stress urinary incontinence. However, further studies are needed to determine overall efficacy and long-term outcomes of stem cell therapy. Using multipotent mesenchymal stem cells to restore the function of the bladder sphincter can lead to proper urinary continence and lack of leakage from the bladder into the urethra.

Neurogenic Bladder

The bladder’s ability to store and eliminate urine is controlled by a complex network of neural pathways. When there is dysfunction in these pathways, a condition termed neurogenic bladder occurs. The symptoms of neurogenic bladder are urinary incontinence, urinary retention, urinary frequency, and urinary tract infections. Neurogenic bladder can be a result of spinal cord injury, as many neural pathways involve the lower levels of the spinal cord. Current therapy includes electrical stimulation, chemotherapy, and surgery, but these methods have significant adverse side effects. There are currently studies examining the use of stem cells in regenerating the spinal cord lesions that result in neurogenic bladder. Stem cells are induced to differentiate into neuronal progenitor cells and are injected directly at the site of spinal cord injury. The L4-L5 spinal cord levels are specifically what affect bladder function and injection of neuronal progenitor cells into those levels has led to improvement of neurogenic bladder from spinal cord injury in animal models. However, more research needs to be done to evaluate the efficacy of this treatment in humans with neurogenic bladder. The ability of stem cells to differentiate into a variety of different tissues, including neural tissue, can theoretically lead to the proper innervation of the bladder and restoration of the bladder’s function and continence.

Bladder Outlet Obstruction

Bladder outlet obstruction can be a result of many conditions, including benign prostatic hyperplasia, that block the flow of urine from the bladder through the urethra. Some signs and symptoms include urinary frequency, urgency and urgency incontinence due to involuntary detrusor muscle contractions, hesitancy and weak flow with urinary retention. If the cause is treated early, there is usually no secondary bladder pathology. However, if the bladder decompensates due to chronic bladder outlet obstruction, there is residual voiding dysfunction due to the loss of bladder smooth muscle as well as hypertrophy of the remainder of the smooth muscle.

Eventually, there is collagen deposition and fibrosis of the bladder as well. Currently, there is no therapy to treat this loss of smooth muscle and fibrosis of the bladder, but there are ongoing studies that attempt to utilize stem cells in regenerating lost smooth muscle. Mesenchymal stem cells from adipose and muscle are induced into differentiating into bladder smooth muscle and implanted into the bladder smooth muscle. By introducing the stem cells into the bladder, there is recovery of bladder smooth muscle and bladder contractility. The implantation of stem cells also resulted in less compensatory hypertrophy of the remainder of the original bladder smooth muscle and decreased fibrosis. In animal models, these stem cell implantations have led to improvement of bladder voiding dysfunction and treatment of the bladder pathology secondary to the initial bladder outlet obstruction. The bladders demonstrated improved voiding capacity and increased contractility. By rejuvenating the lost smooth muscle and preventing fibrosis and hypertrophy of the bladder, stem cell treatments can lead to restoration of normal bladder function in patients who have suffered from chronic bladder outlet obstruction.

Interstitial Cystitis

Painful bladder syndrome, or interstitial cystitis, is a chronic bladder condition that is likely caused by loss of urothelial cells on the interior of the bladder and subsequent exposure of all layers of the bladder to toxic urine contents. This can lead to damage to the bladder wall, which can lead to symptoms such as frequency, urgency, nocturia, and bladder and pelvic pain. There is currently no therapy for interstitial cystitis, but the use of mesenchymal stem cells has been promising in current studies. Biodegradable grafts seeded with stem cells led to regrowth of the urinary bladder wall. Growth factors that these transplanted stem cells released led to regeneration of both the smooth muscle and the urothelial layers of the bladder. So far, studies have shown prevention of interstitial cystitis recurrence and regeneration of damaged bladder wall in subjects treated with stem cell grafts. Since the damaged bladder wall is repaired, there is no longer introduction of the noxious stimuli into the deeper layers of the bladder, which results in reduction of symptoms of interstitial cystitis.

Other Bladder Pathologies

Bilateral iliac artery ligation or hyperlipidemia can lead to changes in bladder structure and function, resulting in bladder ischemia. Ischemia initially leads to the bladder being oversensitive to acetylcholine and therefore leads to over-activity, which worsens the ischemia. This ischemia eventually leads to loss of both neuronal and muscular tissue in the bladder. However, studies have shown that stem cells derived from adipose tissue that are injected into the bladder or given intravenously after differentiating into bladder tissue can lead to regeneration of the smooth muscle and the nerves that were knocked out by the ischemia. This eventually leads to improvement of bladder function and prevention of damage secondary to bladder ischemia.

In diabetic patients, the bladder starts off as overactive and eventually progresses to have both storage and voiding problems, which leads to urinary frequency and urgency. Even later, oxidative stress and neuropathy lead to atonic bladder, wherein the bladder no longer contracts in response to fullness or other stimuli. In animal models, when subjects were treated with adipose-derived stem cells, contractility markedly improved and normal bladder function was restored. This is believed to be due to a paracrine effect from factors released by the stem cells rather than direct differentiation of the stem cells into detrusor smooth muscle.

Krishna S. Vyas

Amit Chakraborty

University of Kentucky College of Medicine

See Also: Bladder: Cell Types Composing the Tissue; Bladder: Existing or Potential Regenerative Medicine Strategies.