Elsevier

European Urology

Volume 61, Issue 1, January 2012, Pages 201-210
European Urology

Sexual Medicine
Recruitment of Intracavernously Injected Adipose-Derived Stem Cells to the Major Pelvic Ganglion Improves Erectile Function in a Rat Model of Cavernous Nerve Injury

https://doi.org/10.1016/j.eururo.2011.07.061Get rights and content

Abstract

Background

Intracavernous (IC) injection of stem cells has been shown to ameliorate cavernous-nerve (CN) injury-induced erectile dysfunction (ED). However, the mechanisms of action of adipose-derived stem cells (ADSC) remain unclear.

Objectives

To investigate the mechanism of action and fate of IC injected ADSC in a rat model of CN crush injury.

Design, setting, and participants

Sprague-Dawley rats (n = 110) were randomly divided into five groups. Thirty-five rats underwent sham surgery and IC injection of ADSC (n = 25) or vehicle (n = 10). Another 75 rats underwent bilateral CN crush injury and were treated with vehicle or ADSC injected either IC or in the dorsal penile perineural space. At 1, 3, 7 (n = 5), and 28 d (n = 10) postsurgery, penile tissues and major pelvic ganglia (MPG) were harvested for histology. ADSC were labeled with 5-ethynyl-2-deoxyuridine (EdU) before treatment. Rats in the 28-d groups were examined for erectile function prior to tissue harvest.

Measurements

IC pressure recording on CN electrostimulation, immunohistochemistry of the penis and the MPG, and number of EdU-positive (EdU+) cells in the injection site and the MPG.

Results and limitations

IC, but not perineural, injection of ADSC resulted in significantly improved erectile function. Significantly more EdU+ ADSC appeared in the MPG of animals with CN injury and IC injection of ADSC compared with those injected perineurally and those in the sham group. One day after crush injury, stromal cell-derived factor-1 (SDF-1) was upregulated in the MPG, providing an incentive for ADSC recruitment toward the MPG. Neuroregeneration was observed in the group that underwent IC injection of ADSC, and IC ADSC treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum.

Conclusions

CN injury upregulates SDF-1 expression in the MPG and thereby attracts intracavernously injected ADSC. At the MPG, ADSC exert neuroregenerative effects on the cell bodies of injured nerves, resulting in enhanced erectile response.

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.

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