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,Massons 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 dosedependent 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.