News and Views
Nature Reviews Urology 10, 8-9 (January 2013)
Subject Category: Sexual dysfunction
Sexual dysfunction: The potential of stem cell therapy for Peyronie disease
Alan W. Shindel About the author
Stem-cell therapy has the potential to regenerate tissue and cure disease—an approach preferable to many current treatments that simply mitigate symptoms. Currently, there is no approved medical therapy for Peyronie disease; a recent study suggests stem cells could provide an intriguing treatment option for this difficult-to-treat tissue defect.
Peyronie disease is not rare; however, treatment of this vexing and poorly understood condition lags far behind the state-of-the-art treatments being developed for erectile dysfunction (ED). To wit, there is no drug or other treatment that has been approved for the management of Peyronie disease by a large regulatory body such as the FDA or the European Medicines Agency.
...there is no drug or other treatment that has been approved for the management of Peyronie disease...
A recent study by Castiglione et al.1—a group of rising and established stars in the field of regenerative urology—investigates the potential for adipose-derived stem-cell (ADSC) therapy for Peyronie disease. The penis is an ideal organ system in which to study regenerative therapies such as gene therapy and stem-cell-based therapy, as the external location of the phallus makes administration of local therapy technically easy compared with treatments intended for visceral organs. Furthermore, the penis contains myriad distinct tissues; regenerative therapies have the potential to exert salubrious effects on a variety of tissue types. Results gleaned from studies on regenerative therapy in the penis could have ramifications for the use of the technique in other vascular, neurologic and connective tissues.
Mesenchymal stem cells (MSCs) have emerged as an appealing alternative to embryonic stem cells.2 MSCs are pluripotent, plentiful, and avoid the ethnical and logistical dilemmas associated with the use of embryonic-derived stem cells. As autologous MSCs could be used, there is also potential for avoiding issues of tissue incompatibility and immunogenicity. Amongst mesenchymal tissue types that can serve as reservoirs of MSCs, adipose tissue offers a number of marked advantages. Adipose tissue is plentiful, accessible, and rarely missed by the donor patient.3 Furthermore, it is rich in the stromal vascular fraction that serves as a source of ADSCs.4 The relative abundance of ADSCs might obviate the need to amplify cells in culture;3 potential benefits of the decreased need for ex vivo manipulation of ADSCs are numerous and include a reduced likelihood of cell transformation during the culture process, lower costs and decreased time interval between cell harvest and clinical application.
Several studies have investigated ADSCs as a management strategy in animal models of ED—ADSCs have been shown to ameliorate impaired penile haemodynamics noted in rodents with diabetes, hyperlipidaemia, cavernous nerve resection and radiation exposure.3, 5, 6 Histological studies have demonstrated an improvement in smooth muscle content, neuronal integrity and decreases in fibrosis and collagen deposition.3, 5, 6 In an intriguing finding, ADSCs appear to have the capacity to migrate in response to cytokine signalling,7 suggesting that these cells migrate to sites of injury; however, additional studies are required to confirm this fascinating finding.
In their recent paper in European Urology, Castiglione et al.1 demonstrate that application of ADSCs to rats treated with intratunical injections of transforming growth factor (TGF)-β1 protects against the development of the Peyronie disease phenotype. The TGF-β1-treated rat is a well established model for Peyronie disease;8 although it is somewhat limited in terms of similarity to the human condition, it is easily the most useful and applicable animal model for the study of the disorder. The team demonstrated preservation of erectile capacity in treated animals (as assessed by ratio of intracavernous pressure to mean arterial pressure during cavernous nerve electrostimulation) as well as reduction in expression of disordered collagen type III and elastin tissues.1 Disordered collagen and elastin tissues are known to be common in Peyronie disease plaques and these proteins are upregulated by application of TGF-β1.9 It follows that modulation of these connective tissues might be an important step in managing the Peyronie phenotype.
An interesting side note for this study is that the authors used human-derived ADSCs from a female subject.1 The use of this technique makes it clear that human ADSCs have the potential to survive in a rat model animal and exert beneficial effects. How and whether the results would differ using same species or even autologous ADSCs is an open question for further research. The potential use of autologous cells is important as patients are likely to have a strong preference for use of their own autologous stem cells.
The precise mechanism of action for ADSCs in amelioration of Peyronie disease, ED, or any other condition for that matter, remains to be elucidated. The prevailing opinion for many years was that stem cells had the capacity to differentiate into target tissues and replace damaged or destroyed cells. More recent evidence suggests that elaboration of cytokines and trophic factors, reduction of inflammation and oxidative stress, and modulation of extracellular matrix might all have roles in stem cell functionality.2 In cavernous-nerve-injured rats, penile injection with a lysate of ADSCs mitigated declines in penile haemodynamic and histological parameters; this result was similar to what was observed with intact ADSC injection.6 This finding begs the question of whether or not the potential risks of injection with intact cells (specifically the potential for migration and differentiation into neoplasms) can be avoided in the future by use of lysed cells or trophic factors. Oncogenicity remains the principle outstanding safety concern with any sort of regenerative therapy; this possibility is a real consideration that is of particular concern given the capacity of stem cells to migrate to remote locations.7 The encouraging data regarding efficacy is a first step but long-term studies of the safety of stem cell therapy in a variety of model systems will be required before human trials of autologous stem cell therapy can become a reality.
Of only slightly lesser interest and concern will be determination of how, exactly, ADSCs exert their beneficial effects.10 The capacity of these cells to effect positive tissue changes across a variety of sites and tissue types is remarkable.10 Even more remarkable is the apparent heterogeneity between tissues types in whether or not stem cell engraftment occurs.10 A more thorough understanding of ADSC effects will permit a more educated application of therapeutic strategies for tissue regeneration.3
1.Castiglione, F. et al. Intratunical injection of human adipose tissue-derived stem cells prevents fibrosis and is associated with improved erectile function in a rat model of Peyronie's disease. Eur. Urol. doi: 10.1016/j.eururo.2012.09.034.
2.Chamberlain, G., Fox, J., Ashton, B. & Middleton, J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25, 2739–2749 (2007).
3.Lin, C. S., Lin, G. & Lue, T. F. Allogeneic and xenogeneic transplantation of adipose-derived stem cells in immunocompetent recipients without immunosuppressants. Stem Cells Dev. 21, 2770–2778 (2012).
4.Lin, C. S. et al. Defining adipose tissue-derived stem cells in tissue and in culture. Histol. Histopathol. 25, 807–815 (2010).
5.Huang, Y. C. et al. The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model. J. Sex. Med. 7, 1391–1400 (2010).
6.Albersen, M. et al. Injections of adipose tissue-derived stem cells and stem cell lysate improve recovery of erectile function in a rat model of cavernous nerve injury. J. Sex. Med. 7, 3331–3340 (2010).