Cell culture expansion of stem cells is often required to reach sufficient cell numbers for treatment purposes. However, current major restrictions regarding the use of cultured cells in human subjects are contamination, unexpected cell differentiation, and tumorigenesis [20
]. Unlike other stem cells that are present at low density in their native tissues, ADSCs have been shown to be abundantly present in adipose tissue [21
]. Most importantly, compared to other stem cell sources such as the bone marrow, large amounts of adipose tissue can be harvested with minimal or no side effects from human subjects. This provides a new perspective to use adipose tissue-derived cells in a clinical setting. Adipose tissue is composed of two main cell populations, mature adipocytes and the SVF. SVF is a heterogeneous fraction containing preadipocytes, mature endothelial cells, vascular smooth muscle cells, macrophages, fibroblasts, and a large population of stem cells and (endothelial and smooth muscle) progenitor cells [15
In the present study, SVF was isolated from adipose tissue and intracavernously injected into rats after CN injury. Compared to previous studies in this setting, there was a notable spontaneous nerve regeneration in untreated animals [18
]. This is likely due to the long time-frame between nerve injury and evaluation. However, this nerve regeneration was significantly improved by SVF injection. It can be speculated that the stem/progenitor cells in the SVF provided the therapeutic effect and preserved erectile function of CN injured rats by producing pro-survival, anti-apoptotic and neurotrophic factors [24
]. We have confirmed these neuroregenerative processes of ADSC in previous studies in which early migration of ADSC towards the MPG was observed [19
This is the first study to examine the effects of stem cells treatment for ED in a chronic state after nerve trauma. Functional recovery and penile histological improvement were observed when treatment was delayed by four weeks at time when neurodegeneration and end-organ damage, including fibrosis, have occurred. The effects of the delayed administration of SVF are in agreement with results from stem cells studies in the central nervous system. Direct injection of bone marrow stromal cells in the brain 2 months after traumatic brain injury resulted in neuroregeneration [26
], and systemic injection of umbilical tissue-derived cells in a similar brain-injury model resulted in locally increased vascular density and decreased apoptosis, thus supporting functional recovery [27
]. In the present study, we found decreased fibrosis in the corpus cavernosum. Whether this effect is secondary to re-innervation and re-oxygenation of the corpus cavernosum, or due to local interaction between stem cells and the extracellular matrix remains undetermined. It has previously been shown that ADSC produce matrix-metalloproteinases that may aid in reducing deposited collagen following corpus cavernosum denervation [28
]. On the other hand, it has been shown that ADSC migrate away from the corpus cavernosum early after injection [19
We believe that this study bridges an important gap in translating the results of previous ADSCs studies towards the clinical setting and application in human subjects. In the current age, SVF is being used in various clinical trials and has proven safe and effective in various settings [17
]. With the observation of beneficial effects of SVF replicating those of ADSC, a novel approach that is directly applicable in the clinical setting has been identified, and initial clinical studies can now be expected within a short time-frame. Liposuction and injection of SVF during the same procedure as radical prostatectomy may be a reasonable treatment option for pre-operatively motivated patients. Furthermore, the positive results of delayed treatment imply that treatment can also be given several weeks following prostatectomy at the time patients begin attempting sexual intercourse.
There are some important limitations to this study. First, ICP/MAP values exceeding 1 were noted in few rats, which may appear supraphysiological. However, ICP can be raised to several hundred mmHg if both the cavernous and pudendal nerves are stimulated [29
]. This may happen during stimulation when the current spreads to the pudendal efferent nerve fibers due to the scars around the MPG and cavernous nerves. The prolonged observation time after injury may have allowed for more extensive scar development. Second, the exact composition of the rat SVF was not examined in this study. However, it is likely that the cell elements in the SVF of the rat are comparable to those in human SVF [30
]. Third, we have not determined whether the decreased fibrosis in the corpus cavernosum is the result of a direct interaction between ADSC and the extracellular matrix or whether this is the result of increased innervation of the corpus cavernosum. Further research is ongoing to determine these interactions and to further understand the effects of cellular therapies in ED following CN injury.