ESSM Newsletter # 39

6 ESSM Today Stem cell therapy in Andrology – are we ready for prime time? by Dorota J. Hawksworth and Trinity J. Bivalacqua Dorota J. Hawksworth, MD, MBA The Johns Hopkins School of Medicine Department of Urology Baltimore, Maryland, USA dhawksw1@jhmi.edu Trinity J. Bivalacqua, MD, PhD The Johns Hopkins School of Medicine Department of Urology Baltimore, Maryland, USA tbivala1@jhmi.edu Stem cell therapy has been in use for the last two decades and is currently utilized to treat many medical conditions including malignant, hematologic, cardiovascular, neurologic and immunologic-based diseases. Recently, great attention has been directed to this form of therapy within the field of Sexual Medicine, as increasing number of basic science stud- ies demonstrate promise in treating erectile dysfunction (ED), Peyronie’s disease (PD) and infertility. [1-3] Stem cells (SCs) are unspecialized precursor cells capable of self-renewal and differentia- tion into various cell types, depending on the stimuli they receive. Based on their origin, they are further sub-classified into embryonic stem cells (ESCs) and adult stem cells (ASCs). ESCs, as their name implies, are derived from the embryonic, inner cell mass of the blastocyst, while ASCs are derived from native tissues of a developed individual. SCs are further di- vided based on their differential potential into totipotent, pluripotent and multipotent. While a fertilized egg is considered totipotent, as it can differentiate into any cell line, ESCs are pluripotent and can differentiate into any cell type with the exception of the fertilized egg. Lastly, ASCs are multipotent and can differenti- ate into organ-specific cell types. In the field of Sexual Medicine, ASCs have been investigated most in pre-clinical settings and in humans with sexual dysfunction. Various types of ASCs have been discovered, with mesenchymal stem cells (MSCs) consti- tuting the largest group. Bone marrow stem cells (BMSCs) are a subgroup of the MSCs that were discovered early on and have been studied thoroughly as treatment option for degenerative and inflammatory diseases. [4] The discovery of adipose-derived stem cells (ADSCs) followed at the turn of the last century and since then ADSCs have been determined to be virtually identical to the BMSCs. [5] Cur- rently, the ease and safety involving adipose tissue abundance and isolation as well as much higher yield of cells from ADSCs than BMSCs, make the former an overall much more attractive form of ASCs. Although ESCs have a much superior dif- ferentiation potential than the ASCs, ethical concerns and regulatory constraints regarding their use hamper their research application. To date, there is only a handful of published studies evaluating use of ESCs, with only one of them performed in a cavernosal nerve injury rat model. In the study, Bochinski et al. dem- onstrated significant beneficial effects of the ESC therapy, with recovery of erectile function and improved quality of the nerve fibers. [6] Other studies focused mainly on male infertil- ity, and demonstrated that ESCs were able to differentiate into male germ cells in vitro and subsequently, those ESC-derived germ cells were able to generate offspring mice. [7] ASC research is advancing at a much faster rate because of the lack of regulatory control and ease of isolation. To date, pre-clinical ani- mal studies in multiple ED models of disease utilizing ASCs-based therapies have been per- formed and established their safety, efficacy and mechanisms of action. The vast majority of the studies are focused on either acute (neu- rogenic) or chronic (diabetes, atherosclerosis, aging and hypogonadism-related) etiologies of ED. All of the rat and rabbit models utilized so far, consistently demonstrated improved erectile function following SC therapy. Additionally, the studies involving animal models of non-obstructive azoospermia also demonstrated significant findings, as they established the ability of the murine BMSCs to differentiate into male germ cells, Sertoli and Leydig cells. [7, 8] Another approach to the SC use is spermatogonial stem cell (SSC) transplantation. This technique was first de- scribed in 1994 when samples of testicular cells from fertile mice were transplanted into infertile mice and resulted in fertility resto- ration. [9] Studies show that following SSC transfer into the recipient animal, SSCs migrate to the basement membrane of the seminifer- ous tubules, self-renew and differentiate to establish spermatogenesis. [10] At present, however, although this use of SCs seems very promising, it remains experimental and has not been attempted in humans. [11] More recently, animal studies in the field of Sexual Medicine are also focusing on the anti- fibrotic properties of ADSCs and their role in attenuation of symptoms related to Peyronie’s disease. So far, scientists found that several molecular signaling pathways are either at- tenuated or activated by ADSC therapy and ultimately result in an increased expression of matrix metalloproteinases (MMPs) respon- sible for collagen degradation, and ultimately suppressed collagen contraction. [2, 12, 13] Now, as the animal models have demonstrated very promising results, over the last few years, researchers have been shifting their focus onto