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Bladder: Development and Regeneration Potential

Since the discovery of stem cells and the understanding of their propensity for self-renewal and differentiation into a variety of cell progenitors, there has been promise for use in cell therapy. The pluripotent nature of stem cells has made them a target for research and development in pathologies affecting all parts of the human body, including the urinary bladder. Urologists have traditionally treated bladder replacement with complicated bowel resection or with less invasive methods such as autologous urothelial or smooth muscle cells. However, this method is not effective in patients where the cells are compromised, like cancer. However, new research has shown that using bone marrow mesenchymal stem cells (MSCs) or human induced pluripotent stem cells (iPSCs) from the skin could have a great impact on tissue regeneration in the bladder because of the differentiation potential of these cells.

The Differentiation Potential of Stem Cells

The research and therapeutic potential of stem cells comes from the cell’s ability to self-renew and also produce progeny cells that can differentiate into many different cell types. These cells are committed progenitors that can go down any one of multiple pathways to create tissue- and organ-specific cell types. Stem cells undergo asymmetric division, producing one cell with a fate to become a differentiated progenitor and one cell that remains as a pluripotent stem cell. This special division and unique ability can be controlled by the microenvironment that surrounds the stem cells. The extracellular components surrounding the cells, secreted signaling proteins, and various cell types surrounding the stem cells play a large role in self-renewal and how the progenitors differentiate into specific cell types. The key to understanding this asymmetrical division and the pathways to differentiation lie in figuring out the minimal signals and extracellular proteins that must be present in the microenvironment to make the stem cells thrive. For stem cells to reach their full therapeutic potential, reaching an understanding of the biology of these cells sufficient to be able to recreate that microenvironment in-vitro is paramount, and the same is true in developing bladder tissue from stem cells.

Bladder Tissue’s Prospective for Regenerative Therapy

Urologists, researchers, and tissue engineers have long been striving for the best methods for bladder reconstruction or regeneration. Stem cell technologies have been considered in pathologies that lead to malfunction or malformation of the bladder, such as spina bifida, interstitial cystitis, stress urinary incontinence, and cancer. For decades, surgeons constructed urinary bladder tissue using the ileum. Later, bowel walls were utilized to recreate urethra and tissue grafts for the bladder. However, this comes with potential complications like adhesions, mucus secretions, metabolic derangements, and even malignant cyst formation. This is also a very invasive procedure. Researchers also harvested autologous urothelial and smooth muscle cells, seeded them onto a biodegradable scaffold, and repopulated those grafts in healthy bladder tissue. This method, however, only works for patients with healthy, uncompromised cells that can be harvested. In cancer patients, the use of autologous bladder cells is too risky to use for tissue grafts. In addition, the size of the bladder surface limits how large a graft can be.

The Development of Stem Cells Into Bladder Tissue

The use of autologous MSCs may be an alternative to current methods in bladder tissue regeneration. Bone marrow MSCs have the potential to differentiate into cell types like chondrocytes, osteoblasts, cardiomyocytes, and skeletal muscle cells. Human embryonic stem cells (hESCs) have great differentiation potential as well, but they are harder to obtain and are not as plentiful to use in research and therapy. Induced pluripotent stem cells (iPSCs) have potential in stem cell research, including induction into urothelium, and is readily accessible without invasive procedures.

The idea remains to harvest iPSCs from hair follicles or MSCs from bone marrow to induce the naïve cells into adult bladder cells for use in regenerative medicine. Many questions are unanswered: Will the differentiated stem cells be viable after transplantation? Can the cells avoid sudden cell death that usually occurs a few hours after implantation? Are the cells capable and sufficient to promote nerve growth and angiogenesis?

A group at Northwestern University looked at a unique alternative to current bladder regeneration methods based around neurological problems arising from the diseases. In spina bifida, for instance, the nerves do not properly convey the messages between the brain and the bladder, and the patient is therefore unable to pass urine normally. Cell therapy presents an opportunity to correct this pathology. The research group combined an elastomer scaffold with similar mechanical properties to the bladder and seeded this scaffold with donor-matched MSCs plus spina bifida hematopoietic progenitor cells. This would use a combination of donor cells but also the patient’s own spina bifida donated cells to decrease rejection. Together, the two types of progenitor cells showed increased tissue vascularization and induction of peripheral nerve growth. These specialized grafts demonstrated urothelium regeneration. This cell regenerative therapy is an attractive alternative to surgical bowel augmentation procedures.

Kurzrock’s group at the University of California–Davis developed a lab protocol to proliferate specialized bladder cells in vitro utilizing autologous iPSCs taken from human skin cells, which lowers the risk for rejection. The method of reliably differentiating stem cells can lead to greater testing of new bladder tissue to check for true regeneration, continued viability, and the ability to repair itself just like real tissue would. It’s the first method used to differentiate stem cells into specialized tissue without the use of a dedicated matrix or scaffold and without cell contact of any kind.

Developing stem cells into a viable treatment for bladder dysfunction eliminates some of the disadvantages of current methods. These treatments can eliminate invasive surgery like augmentation cystoplasty and the complications that could arise. Using a patient’s own cells for therapy eliminates the risk of immunologic rejection.

Human stem cells do need further testing before they can become a viable therapy. The differentiated cell products need to be completely pure, adult, differentiated cells without pluripotent cells that could cause issues when transplanted. To become a reliable therapy, the growth conditions and methods for differentiating stem cells needs to be consistent and replicable. The signals that cause differentiation need to be elucidated and the microenvironment needs to be well defined.

Beyond the Boundaries of Urothelial Stem Cell Differentiation

The scope of current studies is to relieve the complications of bowel resection and broaden the scope of regeneration of bladder tissue for all kinds of bladder pathologies. A healthy side-effect of discovering methods to differentiate hESCs, iPSCs, and MSCs into viable, healthy, lasting bladder cells is more than just the ability for replacing tissues and organs.

When researching the methods and proper signals needed to differentiate those pluripotent cells, scientists believe there is also potential to learn about the pathways that cause such diseases or malformations. Scientists speculate that this could lead to a greater understanding of the signals, cell components, and microenvironment that are responsible for bladder pathology and self-repair processes. There has also been suggestion that the bladder cell lines created, as a renewable, reliable source of in vitro cell models, could be a useful tool to test drug toxicity and clinical therapies before transition to animal models. These cell lines that are created can also be used to study cancer pathways and treatment targets. In addition, ongoing studies in bladder regenerative research increases the likelihood of successful strategies for other types of tissue and regenerative medical therapies.

Stem Cells Showing Promise in Regenerative Therapy of the Bladder

Human embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells are all potential sources of adult differentiated bladder cells. Grafts, scaffolds, and new cells need to be scaled up to a small animal model and then a larger animal model before use in human clinical trials. The methods of using stem cells for augmenting damaged tissue or full organ replacement need to be proven to avoid sudden cell death after transfer and prove long-term viability in the bladder. The cells need to be fully differentiated so there is no regression after implantation in the bladder. Using the patient’s own stem cells for differentiation lowers the risk of immunologic graft rejection and because of the self-renewal nature of stem cells, provides a resource for continued cell therapy if needed. The ability to reliably direct and differentiate pluripotent stem cells in the bladder shows promise toward the future, but also holds promise and insight into other types of tissue that can be used in regeneration from stem cells.

Mark Rodgers

University of Pittsburgh School of Medicine

See Also: Bladder: Current Research on Isolation or Production of Therapeutic Cells; Bladder: Existing or Potential Regenerative Medicine Strategies; Bladder: Stem and Progenitor Cells in Adults.