Filtrated bone marrow-derived stem cell lysate may improve erectile function through nerve regeneration in a rat model of cavernous nerve injury

Abstract

ABSTRACT Introduction Oral phosphodiesterase-5 (PDE5) inhibitors and intracavernous injection of prostaglandin E1 (PGE1) are common therapies for erectile dysfunction (ED) following radical prostatectomy (RP). However, these treatments are not always effective, and the development of a novel and effective therapy for ED following RP is required. Recently, mesenchymal stem cell (MSC) transplantation was shown to induce nerve regeneration and improves erectile function in a rat model of bilateral cavernous nerve injury (BCNI), a routinely used animal model of RP. Thus, MSCs are expected to be a novel therapy for ED following RP. However, the known risks of stem cell therapy include induction of embolization and immunoreactions. To avert these problems, we explored the suitability of using filtrated stem cell lysate, which contains secreted factors but does not contain MSCs. Objective In this study, we investigated the effects of filtrated bone marrow-derived stem cells lysate (BSCL) on erectile function in a rat model of BCNI. We also investigated the neuroregenerative effects of BSCL using the major pelvic ganglia (MPG) of rats. Methods Bone marrow-derived stem cells were obtained from Wistar/ST rats. After culturing two or three passages, these cells were collected and diluted with phosphate buffered saline (PBS). We obtained BSCL by freeze fracturing and filtrating them. Two experiments were performed. Experiment I: Eight-week-old male Wistar/ST rats were divided into three groups: Sham+PBS (n=8), BCNI+PBS (n=8), and BCNI+BSCL (n=8). Rats in the Sham+PBS group underwent sham surgery as a control. Rats in the BCNI+PBS group underwent complete BCNI surgery. After both surgeries, PBS was injected into the corpus cavernosum. Rats in the BCNI+BSCL group also underwent BCNI surgery, but after surgery, BSCL was injected into the corpus cavernosum. After 4 weeks, erectile function was evaluated by measuring intracavernosal pressure (ICP)/mean arterial pressure (MAP) under stimulation of the cavernous nerve. Experiment II: the MPG were dissected from ten-week-old male Wistar/ST rats. The MPG were placed on Matrigel and incubated with PBS (n=4), BSCL (n=4), or vascular endothelial growth factor (VEGF) (n=4), which was used as a positive control. After 48 h, neurite outgrowth was measured using a z-stack microscope. Results ICP/MAP in the BCNI+PBS group was significantly lower than that in the Sham+PBS group (P<0.05), and ICP/MAP in the BCNI+BSCL group was significantly higher than that in the BCNI+PBS group (P<0.05). MPG treated with BSCL and VEGF had longer neurite outgrowth than those treated with PBS. Conclusions BSCL treatment improved erectile function in the BCNI rat model of RP. BSCL also exhibited neuroregenerative effects on rat MPG. This suggests that BSCL may regenerate a crushed cavernous nerve, which results in improved erectile function. Our findings suggest that BSCL may be a new approach for post-RP ED. Further study should be conducted to identify the active factors in BSCL. Disclosure Work supported by industry: no.