Sexual MedicineRecruitment of Intracavernously Injected Adipose-Derived Stem Cells to the Major Pelvic Ganglion Improves Erectile Function in a Rat Model of Cavernous Nerve Injury
Introduction
Nerve-sparing radical prostatectomy is the treatment of choice for localized prostate carcinoma in sexually active men [1]. Despite technical and anatomical advances, erectile dysfunction (ED) remains a major complication of this surgery [2]. Phosphodiesterase type 5 inhibitor therapy is a commonly used first-line treatment for ED following bilateral nerve-sparing radical prostatectomy in ad hoc and erectile rehabilitation schemes [3]. However, due to the limitations in nerve regeneration, these drugs remain largely inefficient in this population [4].
Recently, stem cell-based therapy has garnered attention as a potential alternative in the prevention of ED following cavernous nerve (CN) injury. Embryonic stem cells transduced with brain-derived neurotrophic factor and adult bone marrow-derived stem cells were capable of preserving erectile function via intracavernous (IC) application [5], [6], [7]. Despite these encouraging results, the clinical applicability of these cell types is limited due to scant availability and ethical concern [8]. In contrast, adipose-derived stem cells (ADSC) have emerged as one of the most promising stem-cell types [9]. ADSC represent an abundant and easily accessible source of stem cells. While stem cells from both sources can be easily expanded in culture, adipose tissue can be obtained in large amounts with a minimal invasive procedure, and this may exclude the need for in vitro expansion. Furthermore, ADSC lack the ethical burden of the use of embryonic material. IC injection of ADSC has been shown efficacious in restoring damaged nerves and improving erectile function in a CN-injury ED rat model [10].
One common feature in the above-mentioned studies is the administration of stem cells through IC injection. However, despite its apparent therapeutic efficacy, the mechanism of action of this stem-cell transplantation approach has never been investigated. This kind of information is essential before future human clinical trials can be initiated [11]. The present study was designed to examine the fate of ADSC after IC injection following CN injury and to evaluate the mechanisms of action linked to the observed enhancement of erectile function.
Section snippets
Study design
A total of 110 male Sprague-Dawley rats (aged 3 mo) were obtained from Charles River Laboratories (Wilmington, MA, USA). After harvest of paratesticular fat in all animals, 10 random animals served as noninjected sham controls (group 1) (Table 1). The remaining 100 rats were randomly divided into four equal groups (Table 1; Fig. 1): IC injection of ADSC without prior CN crush (group 2); IC injection of phosphate-buffered saline (PBS) after bilateral CN crush (group 3); IC injection of ADSC
Intracavernous but not perineural injection of adipose-derived stem cells, prevents cavernous nerve injury–induced erectile dysfunction
Erectile function was assessed by electrostimulating the distal end of CN at 28 d postsurgery in all groups (Table 2; Fig. 2). Sham-treated rats with or without IC injection of ADSC displayed normal ICP curves and the ICP-to-MAP ratios did not differ significantly (data not shown). CN crush consistently resulted in significantly decreased ICP-to-MAP ratios. ED was ameliorated by IC injection of ADSC, as rats in the Crush + ADSC group showed significantly improved ICP-to-MAP ratios. However,
Discussion
Various reports have illustrated the efficacy of stem cells in animal studies of ED [5], [6], [7], [10], [15], [16]. This study was conducted in a series of experiments aimed at demonstrating efficacy of ADSC in a postprostatectomy model of ED and elucidating the mechanisms of action of this cell-based regenerative therapy. The current study clarifies in detail how ADSC possibly exert their neurotrophic effects.
IC injection was employed for the administration of stem cells in all published
Conclusions
These data, in conjunction with previous investigations, indicate that IC injected ADSC, and possibly other types of stem cells, exert their proerectile effects after CN injury by recruitment toward the MPG, where they initiate neural regeneration in the MPG.
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These authors contributed equally.