Anthony J. Bella MD,and Tom F. Lue MD
Knuppe Molecular Urology Laboratory, Department of Urology, University of California, San Francisco, CA.
Stem cells (SC) hold unparalleled future therapeutic promise and have captured the imagination of the public at large and scientists in a variety of fields. Although claims that SC will someday cure all of today’s untreatable diseases must be tempered, real possibilities exist that advances will result in novel therapies treating a wide range of congenital or acquired disease, a renewable source of tissues, and further understanding of developmental physiology and the pathophysiology of malignancies. In urology, SC offer potential treatment for neurogenic or diabetic voiding dysfunction, stress urinary incontinence, infertility, and cancer, tissue-specific graft materials for Peyronie’s disease, and therapies for erectile dysfunction (ED). In this article, we review basic SC progress made to-date within the context of sexual medicine, and remark upon future opportunities for this class of treatments.
What characterizes a stem cell ?
Although SC may be derived from various sources, they possess three essential characteristics: 1) Self-renewal, or the ability to maintain a population of cells that possess the same qualities as the original (progenitor) cells, through cell division, 2) proliferation through mitosis, and 3) a capacity to proceed to various cell types via differentiation; cells are unique from the parent or progenitor cell in gene expression and also from each other . An undifferentiated SC self-renews to maintain the stem cell pool and at the single-cell level, differentiates into more than one mature, functional cell. When transplanted, SC should be capable of replacing a damaged organ or tissue for the lifetime of the recipient, and some propose that SC are also capable of functionally integrating into non-damaged tissues .
Sources of stem cells
Initial strategies focused upon the use of embryonic stem cells (ESC). However, procurement and preservation of ESC for therapeutic use in humans has been limited by ethical concerns, political controversy and technical challenges. Adult tissue derived stem cells offer an alternative to ESC, amniotic fluid, and fetal stem cells. Adult adipose tissue derived stem cells (ADSCs) represent a population of mesenchymal stem cells extracted from adult fat tissue, providing an abundant, accessible, and replenishable source of pleuripotent and multipotent cells which may be better suited for potential clinical applications. including  The various sources of stem cells are reviewed below:
Embryonic Stem Cells (ESC)
ESC are the most pleuripotent stem cells, derived from the inner cell mass of the blastocyst when the human embryo is still a hollow sphere. ESC are formed in the first week of development, and are the ‘master cell’ from which all other cells (over 200 types) will ‘stem’. ESC can be coaxed along various paths of differentiation (ie. osteoblasts, muscle cells, etc). For example, neural cell-line induction medium may consist of insulin, indomethacin (INDO), and isobutylmethylxanthine (IBMX); insulin promotes cell maturation, INDO (a cyclooxygenase inhibitor) promotes neural cell survival, and IBMX (non-specific phosphodiesterase inhibitor) is a neural stimulus . Alternatively, ESC may be separated according to type after spontaneous differentiation or induced towards specific cell lines via gene transduction. Although human ESC have revolutionized regenerative medicine by allowing the establishment of detailed molecular and therapeutic models for certain metabolic pathways and life-threatening disorders, the procedures by which they are obtained and manipulated have created intense ethical and social debates worldwide, thereby potentially limiting direct translational potential . Furthermore, ESC use is currently limited by the propensity of cells to spontaneously differentiate into tumors, specifically teratomas, and unrelated cell types when introduced in vivo.
Somatic Cell Nuclear Transfer Therapeutic Cloning, Fetal and Amniotic Fluid Stem Cells
The transfer of a nucleus of an adult cell into an unfertilized egg, and resultant growth of an embryo in culture via somatic cell nuclear transfer therapeutic cloning (SCNT) allows for extraction of the inner cell mass and cells with comparable qualities to ESC. SCNT is ethically charged, as the process yields embryos that theoretically could lead to growth of a clone, having the genetic make-up of the original differentiated adult cell. A distinct advantage is the possibility that such cells could be transplanted back into the human donor without immunologic rejection . Fetal stem cells (FS) may represent an intermediate cell type between adult versus ESC, as first-trimester fetal blood, liver, and bone marrow contain a population of mesenchymal stem cells with multipotentency. However, extraction techniques without morbidity to the developing fetus are yet to be fully defined. Finally, Atala et al recently reported the isolation of broadly multipotent human and rodent amniotic fluid-derived stem (AFS) cells expressing embryonic and adult stem cell markers and differentiating into neuronal, hepatic, and osteogenic cell lines . FS and AFS may ultimately represent valuable options to ES and SCNT, where the embryos are destroyed.
Adult Stem Cells
The isolation and use of adult stem cells (ASC) would allow for ease-of-transition to clinical applications, eliminate immune rejection complications, and bypass the ethical dilemmas of ES and SCNT. Mesenchymal stem cells (MSC) have been harvested from human bone marrow and other sources including skin, skeletal muscle, etc, and are capable of differentiation into multiple cell lines. Isolation is, at times, difficult due to the low ASC numbers amongst normal cells . Also, a significant limitation of bone-marrow derived MSC (BM-MSC) is the invasive nature and morbidity associated with tissue harvest and apparent dependence on target tissue-specific induction factors. The pleuripotent fraction of adipose-tissue cells residing in the stromal fraction of adult fat tissue occurs 500 times more frequently than BM-MSC . Fat tissue is relatively expendable, available in sufficient quantities, and can be obtained with minimal risk to the donor. Human ADSCs have demonstrated the capacity to differentiate into osteoblasts, cardiomyocytes, endothelial and neural cell types in the presence of lineage-specific induction factors; reports indicate that non-transduced and undifferentiated ADSCs have formed bone in an experimental mouse model, and importantly, have been applied safely in a clinical case of calvarial (skull) reconstruction .
Stem cells and Sexual Medicine
Post Radical-Prostatectomy Erectile Dysfunction
Despite advanced techniques for the curative management of pelvic malignancies, surgical manipulation or radiation inadvertently causes cavernous nerve damage even when nerve-sparing approaches are utilized. Most men report varying degrees of compromised erectile function or complete loss of potency, defining a clear clinical need for the development of neuroprotective or neuroregenerative strategies after cavernous nerve injury .
Using stem cell therapy for neurogenic ED is an attractive concept; the time of injury is known prior to surgery, the external location of the penis allows for intracavernous introduction and retrograde transport of potential therapeutic agents to the site of injury, and the functional endpoint (penile erection) is measurable in both animal models and humans. ESC that have differentiated along neuronal cell lines have been injected into the corpus cavernosum, influencing cavernosal nerve regeneration and functional erectile status after bilateral crush injury in the rat; maximal increases in intracavernous pressure at three months was markedly enhanced for ES treated groups, and examination of penile nerves demonstrated a greater degree of nerve regeneration . Subsequently, we have demonstrated that adult ADSCs allow for increased in vitro neurite growth from the major pelvic ganglion (from which the cavernous nerves originate) and that in vivo erectile recovery is enhanced to near-normal levels after intracavernous injection of autologous ADSCs in 50% of rats studied (unpublished results). The most intriguing aspect of the latter investigation is that ADSCs were not influenced towards a particular lineage; rather, the fraction of adipose tissue containing pleuripotent cells was isolated, and then injected into the penis.
Aging, Diabetes and Erectile Dysfunction
Aging and diabetes are two well-known risk factors for ED; stem cell treatments may enhance erectile function in these often difficult-to-treat patients. Bivalacqua et al have recently demonstrated the feasibility of reversing age-related decline in erectile function using BM-MSC alone or with ex vivo gene modification to allow for expression of endothelial nitric oxide (NO) synthase by these cells . The stem cells survived for at least 21 days after corporal injection, improved endothelial-derived NO/cyclic guanosine monophosphate signaling, and expressed endothelial and smooth muscle cell markers indicative of differentiation into local penile tissue cells. Several targets have also been identified for therapies for diabetes-induced ED, including the modulation endothelial changes .
Peyronie’s Disease and Penile Reconstruction
In addition to the development of stem cell embedded or tissue-specific biomaterials for use as graft materials in reconstructive approaches to Peyronie’s disease, the entire corpora has been engineered for total penile replacement in the rabbit, achieving adequate structural and functional parameters sufficient for copulation, ejaculation, and conception [15,16]. Successful translation of this technology may be potentially useful in patients with severe corporal fibrosis or penile trauma.
Stem cell advances have led to a surge of clinical interest for the development and application of novel treatments. Sexual medicine may reap the benefit of ongoing research in the not-too-distant future, as laboratory findings are translated into patient care, with particular potential demonstrated for approaches utilizing adult tissue derived stem cells.
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