which they may be cultured. There has been a great deal of research on bone marrow-derived cells’ differentiation into osteocytes, adipocytes, chondrocytes, hepatocytes, and myocytes. There even exists a possibility of differentiation into cardiomyocytes and neurons. Because MSCs were noted to differentiate into various cell lines, it was thought initially that the mechanism by which MSC acted was through engraftment and differentiation into the injured tissue. In the bladder, research was focused on tissue regeneration, with hope of enabling an autologous bladder augmentation and circumventing the various morbidities associated with enterocystoplasty.
Ideally, clinicians would use bladder tissue regeneration to develop a functional urinary bladder for patients with either congenital or acquired bladder defects. Current strategies include augmenting a poorly functioning fibrotic bladder, reconstructing a partially removed bladder, or developing a reservoir from intestine. Bladder tissue regenerative studies involve using an underlying matrix that is seeded with cells or left unseeded for in vivo infiltration. There is exceptional enthusiasm in the realm of bladder tissue engineering with MSCs as donor cells at the forefront.
Research on Production and Regeneration of Epithelial Stem Cells in the Bladder
Some organ epithelial tissues, such as the intestine, regenerate constantly, which allows them to remain continuously proliferative. Other organs, such as the urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury. Up until recently, the cellular mechanisms involved with this injury-induced mode of regeneration has been poorly defined. Studies involving mice have shown that the proliferative response to bacterial infection within the bladder is regulated by a special feedback mechanism between basal cells of the urothelium and the stromal cells that underlie them. Essentially, these basal cells include stem cells capable of regenerating all cell types within the urothelium, which can be key in bladder regenerative medicine strategies. These basal cells are marked by the expression of a special protein that increases and elicits stromal expression of other protein signals. This biochemical process results in stimulation of proliferation of both urothelial and stromal cells. The increased signal feedback circuit activity and the related increase in cell proliferation have been shown to be required for the restoration or urothelial function.
Research Using Marrow-Derived Cells in Smooth Muscle Cells
The bladder is unique in that it requires smooth-muscle cell regeneration. The mechanisms by which this occurs are being investigated. In a 2004 study, bone marrow cells were transplanted in vivo into lethally irradiated rats. By 12 weeks, they reconstituted the smooth-muscle layer with native smooth-muscle cells infiltrating the graft. This in vivo study identified that marrow cells differentiate into smooth muscle on acellular matrix grafts in response to the environment created by smooth-muscle cells. In vitro aspects of the experiment aimed to identify the effect of the special growth factor environment created by either the bladder urothelial cells or the bladder smooth-muscle cells on phenotypic changes of the marrow cells were examined. The results indicated a growth factor characteristic of smooth-muscle cell induced a phenotype similar to smooth-muscle cell in the bone marrow cells. In contrast, urothelial cells failed to induce the smooth-muscle cell-like phenotype.
Bladder Cells Derived From Umbilical Cord Blood and Skin Cells Stem Cells
The human bladder is lined with a specialized cell group called the urothelium. Urothelium is found throughout the urinary tract and it is very elastic. Guiding stem cells to develop into a proper urothelium has proved troublesome. Scientists have succeeded in devising a method for converting differentiating human pluripotent stem cells into urothelial cells. Two types of induced pluripotent stem cells were used. Genetically modified human skin cells and genetically modified umbilical cord blood cells were used to create bladder cells. These stem cells were successfully differentiated into bladder cells. Not only did the newly produced cells look like urothelium, but they also expressed a specific protein that is unique to the bladder and helps make it impermeable to toxins found in urine.
Krishna S. Vyas
University of Kentucky College of Medicine
Shalin Jyotishi
University of Georgia
See Also: Bladder: Development and Regeneration Potential; Bladder: Stem and Progenitor Cells in Adults; Cord Blood Stem Cells; Mesenchymal Stem Cells.
Further Readings
Bharadwaj, Shantaram, et al. “Multi-Potential Differentiation of Human Urine-Derived Stem Cells: Potential for Therapeutic Applications in Urology.” Stem Cells, v.31/9 (2013).
Drzewiecki, Beth, John Thomas, and Stacy Tanaka. “Bone Marrow-Derived Mesenchymal Stem Cells: Current and Future Applications in the Urinary Bladder.” Stem Cell International, v.2010 (2010).
Osborn, Stephanie, et al. “Induction of Human Embryonic and Induced Pluripotent Stem Cells Into Urothelium.” Stem Cells Translational Medicine (March 2014).
Shin, Kunyoo, et al. “Hedgehog/Wnt Feedback Supports Regenerative Proliferation of Epithelial Stem Cells in Bladder.” Nature, v.472 (2011).
Weinberg, Robert and Chiaho Shih. “Isolation of a Transforming Sequence From a Human Bladder Carcinoma Cell Line.” Journal of Tissue Engineering and Regenerative Medicine, v.2/4 (2008).
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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
