Bladder: Current Research on Isolation or Production of Therapeutic Cells
Bladder: Current Research on Isolation or Production of Therapeutic Cells
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Bladder: Current Research on Isolation or Production of Therapeutic Cells
Cellular therapy is a form of medical treatment in which cellular material is injected into a patient. In mainstream medicine, cell therapy is a subject of increasing interest and holds the basis of potential therapeutic benefit. There exists a great potential to use cellular therapy in the treatment of the urinary bladder. Current research on isolation and production of therapeutic cells in the bladder originates from stem cell studies carried out on various sources of these cells. In this article, these origins will be addressed.
Because stem cells maintain the capacity for self-renewal and the ability to differentiate into various cell lineages, they represent an important building block for bladder regenerative medicine strategies. These cells can broadly be classified into embryonic stem cells and nonembryonic cells, also known as adult stem cells. Embryonic stem cells have promising potential; however, researchers are prohibited from studying them, due to ethical and scientific considerations. The use and the study of isolated cells from the bone marrow, umbilical cord, adipose tissue, skin, and amniotic fluid-derived mesenchymal stem cells might be a good alternative for translational activities.
A urinary bladder (black butterfly-like shape) and hyperplastic prostate (BPH) visualized by medical ultrasonography. Stem cells represent an important building block for bladder regeneration. (Wikimedia Commons/Etan J. Tal)
Research on Stem Cells From Urine
Researchers at Wake Forest Baptist Medical Center’s Institute for Regenerative Medicine have identified stem cells in urine that may be differentiated into various cell types. Previously, the team first identified cells that are a small subset of many cells found in urine. The current research furthers the previous studies by confirming the multipotency of the cells. Isolating the cells from urine constitutes relatively minimal processes, according to the researchers. The cells differentiated into three tissue layers, called germ layers: the endoderm, the ectoderm, and the mesoderm. The germ layer is the primary layer of cells that form during embryogenesis. Germ layers eventually give rise to all of an animal’s tissues and organs through organogenesis. This characteristic is a hallmark of true stem cells.
The research team was also able to successfully direct stem cells from urine to become bladder-type cells such as urothelial and smooth muscle, which line the bladder. However, one of the most interesting aspects of the research team’s findings was that the urine-derived cell line may also be used to develop bone, fat, skeletal muscle, nerve, and endothelial cells, which line various blood vessels in the body. The research carried out by the Wake Forest team holds promise for cellular therapy of the bladder and other organs.
The derived stem cells represent virtually an infinite supply of autologous cells to use for medical treatments, not only urology-related such as kidney disease but also erectile dysfunction and urinary incontinence. The cells may potentially also be used to engineer replacement bladders, urine tubes, and other urologic organs. The ability to use a patient’s own stem cells for therapeutic use is highly desirable by clinicians because they do not result in any immune responses or rejections. Stem cells formed using foreign sources may result in immune rejection, which complicates medical treatments. Because tissue-specific cells constitute a very small subpopulation of cells, they can often be difficult to isolate from tissues and organs in the body. Furthermore, unlike induced pluripotent stem cells or embryonic stem cells, the urine-derived stem cells do not form tumors when implanted in the body, which may prove them to be safe for use in patients. The research team suspects that the cells originated from the upper urinary tract, including the kidney. Female study participants who received kidney transplant from male donors were found to have the Y chromosome in their urine-derived stem cells, which suggests that the kidneys may be the source of the cells. Identifying the origins of the urine-derived cells will lead to a clearer understanding of the biological function of multipotent populations of mesenchymal cells within the urinary tract system.
Research on Stem Cells From Bone Marrow
Mesenchymal stem cells can be isolated from virtually any adult tissue. Researchers have been examining ways to use bone marrow-derived mesenchymal stem cells for tissue repair and regeneration of the urinary bladder. MSCs are an adult stem cell isolated from a variety of adult tissue, including bone marrow, adipose, liver, lung, kidney, and skeletal muscle.
A distinct advantage of bone marrow isolates is the ease with 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