AB047. Activating and mobilizing endogenous stem cells: a novel therapeutic approach for erectile dysfunction

Background and Objective: Transplanted stem cells (SCs), owing to their regenerative capacity, represent one of the most promising methods to restore erectile dysfunction (ED). However, insufficient source, invasive procedures, ethical and regulatory issues hamper their use in clinical applications. The endogenous stem/progenitor cells resident in organ and tissues play critical roles for organogenesis during development and for tissue homeostasis in adulthood. Even without any therapeutic intervention, human body has a robust self-healing capability to repair the damaged tissues or organs. Therefore, SCs-for-ED therapy should not be limited to a supply-side approach. The resident endogenous SCs existing in patients could also be a potential target for ED therapy. The aim of this study was to observe the changes of erectile function and histopathological injury of penis in a rat model of bilateral cavernous nerves (CN) injury. To investigate the therapeutic effects of IcarisideII (ICAII) in the neurogenic ED. To explore its underlying mechanisms of ICAII in ameliorating erectile function and pathological changes.

Methods: 60 newborn male SD (Sprague Dawley) rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous SCs by using label-retaining cells (LRCs) approach. Twelve weeks later, 48 rats underwent bilateral cavernous nerves injury and were randomized into gavage feeding of solvent (vehicle group) or ICA II (0.5 mg/kg/day, n=12; 1.5 mg/kg/day, n=12; and 4.5 mg/kg/day, n=12). Twelve sham-operated rats received vehicle treatment and served as control. The treatments were continued for 4 weeks followed by a washout period of 72 h, and then intracorporal pressure (ICP)/mean arterial pressure (MAP) was measured by CN electrostimulation to assess penile erectile function. Penile samples were harvested with subsequent histopathological staining and molecular biological test, including immunofluorescent staing, Masson`s trichrome stainging and Western blot.

Results: The data showed that CN crush injury caused significant decreases of ICP/MAP ratio, the number of nNOS-positive nerves and smooth muscle content in the vehicle-treated group compared to the sham-treated rats. In addition, axon degeneration and penile fibrosis were also evident in the CN injury-induced rats with vehicle treatment, shown by axonal swelling vacuolization and penile interstitial collagen deposition. Results showed that ICA II treatment significantly increased the ICP/MAP ratio and the number of nNOS-positive, and effectively prevented distortion of normal neural anatomy, smooth muscle atrophy, and collagen deposition in a dose-dependent manner as compared with the vehicle group. The numbers of label-retaining cells (LRCs) coexpressing EdU and differentiated phenotypes (smooth muscle marker a-SMA or Schwann cell marker S100) were significantly higher in the three ICA II-treated groups than those in vehicle group in a dose-dependent manner. In addition, the changing trend of p38 mitogen-activated protein kinase (MAPK) activity in the penis between groups was same as that of the number of differentiated LRCs.

Conclusions: ICA II could significantly improve erectile function and pathological injuries in the rat model of bilateral CN injury. Its underlying mechanisms of ICA II in ameliorating erectile function and pathological changes appear to involve enhanced endogenous SCs differentiation into smooth muscle cells and Schwann cells, which might be regulated by p38 MAPK signaling pathway.

Keywords: Icariside II; erectile dysfunction (ED); endogenous stem cell (endogenous SC); p38 mitogen-activated protein kinase (MAPK)