Umbilical Cord Blood Mesenchymal Stem Cells Relieve the Symptoms of Interstitial Cystitis by Activating the Wnt Pathway and EGF Receptor

Interstitial tissue refers to the tissue that lies between major structures in an organ. For example, the tissue between muscles is an example of interstitial tissue.

Interstitial cystitis, otherwise known as painful bladder syndrome is a chronic condition that causes bladder pressure, bladder pain and sometimes pelvic pain, ranging from mild discomfort to severe pain.

The bladder is a hollow, muscular organ that stores urine and expands until it is full, at which time it signals the brain that it is time to urinate, communicating through the pelvic nerves. This creates the urge to urinate for most people. In the case of interstitial cystitis, these signals get mixed up and you feel the need to urinate more often and with smaller volumes of urine than most people. Interstitial cystitis most often affects women and can have a long-lasting impact on quality of life. Unfortunately no treatment reliably eliminates interstitial cystitis, but medications and other therapies may offer relief. There is no sign of bacterial infection in the case of bacterial cystitis.

A new study evaluated the potential of umbilical cord blood-derived mesenchymal stem cells or (UCB-MSCs) to treat interstitial cystitis (IC). In this study, Dr. Miho Song and colleagues from the Asan Medical Center, Seoul, South Korea, established a rat model of IC in 10-weeks-old female Sprague-Dawley rats by instilling 0.1M HCl or PBS (sham). After 1-week, human UCB-MSCs (IC+MSCs) or PBS (IC) were directly injected into the submucosal layer of the bladder.

To clarify this part of the experiment, the urinary bladder is made of several distinct tissue layers: a) The innermost layer of the bladder is the mucosa layer that lines the hollow lumen. Unlike the mucosa of other hollow organs, the urinary bladder is lined with transitional epithelial tissue that is able to stretch significantly to accommodate large volumes of urine. The transitional epithelium also provides protection to the underlying tissues from acidic or alkaline urine; b) Surrounding the mucosal layer is the submucosa, a layer of connective tissue with blood vessels and nervous tissue that supports and controls the surrounding tissue layers; c) The visceral muscles of the muscularis layer surround the submucosa and provide the urinary bladder with its ability to expand and contract. The muscularis is commonly referred to as the detrusor muscle and contracts during urination to expel urine from the body. The muscularis also forms the internal urethral sphincter, a ring of muscle that surrounds the urethral opening and holds urine in the urinary bladder. During urination, the sphincter relaxes to allow urine to flow into the urethra.

Bladder histology

Now a single subcutaneous injection of human UCB-MSCs significantly attenuated the irregular and decreased voiding interval in the IC group. In addition, the denudation of the epithelium that is characteristic of IC and increased inflammatory responses, mast cell infiltration, neurofilament production, and angiogenesis observed in the IC bladders were prevented in the IC+MSC group. Therefore, the injected UBC-MSCs prevented the structural changes in the bladder associated with the pathology of IC.

How did these cells do this? Further examination showed that the injected UCB-MSCs successfully engrafted to the stromal and epithelial tissues of the bladder and activated the Wnt signaling cascade. In fact, if the Wnt activity of these infused cells was blocked, the positive effects of the UCB-MSCs were also partially blocked. Additionally, activation of the epidermal growth factor receptor (EGFR) also helped UCB-MSCs heal the bladder. If the activity of the EGF receptor was inhibited by small molecules, then the benefits of MSC therapy were also abrogated. Also if both the Wnt pathway and EGFR were inhibited, the therapeutic capacities of UCB-MSCs were completely wiped out.

These data show the therapeutic effects of MSC therapy against IC in an orthodox rat animal model. However, this study also elucidates the molecular mechanisms responsible for these therapeutic effects. Our findings not only provide the basis for clinical trials of MSC therapy to IC, but also advance our understanding of IC pathophysiology.