Implications for Differentiation of Endogenous Stem Cells: Therapeutic Effect from Icariside II on a Rat Model of Postprostatectomy Erectile Dysfunction

Abstract

Self-renewal and differentiation of endogenous stem cells (SCs) are essential for adult tissue homoeostasis and intrinsic healing capacity. In this study, we hypothesize that penis contains a small population of endogenous SCs, which might help rejuvenation of damaged erectile function. In this study, 60 newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous SCs. Twelve weeks later, 48 rats underwent bilateral cavernous nerves injury and were randomized into gavage feeding of solvent (vehicle group) or icariside II (0.5, 1.5, and 4.5 mg/kg/day, respectively). 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. Results showed that ICA II treatment significantly restored erectile function and effectively prevented distortion of normal neural anatomy, smooth muscle atrophy, and collagen deposition compared with the vehicle group. The numbers of label-retaining cells (LRCs) coexpressing EdU and differentiated phenotypes (smooth muscle marker α-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. Together, these results suggest that the underlying mechanisms of ICA II in ameliorating erectile function and pathological changes appear to involve enhanced endogenous SCs differentiation, which might be regulated by p38 MAPK signaling pathway.

Effect of icariin in combination with daily sildenafil on penile atrophy and erectile dysfunction in a rat model of bilateral cavernous nerves injury

“…Our previous works have demonstrated that penis contains small populations of endogenous SCs by LRC strategy Xu et al, 2015) . Stem/progenitor cells, residing in various types of organs, play a critical role in homeostasis and wound repair.…”

“…These label retaining cells (LRC) are generally considered as putative SCs because of their asymmetric division, slow-cycling and quiescent features. Our previous works have demonstrated that penis contains small populations of endogenous SCs by LRC strategy Xu et al, 2015) . Schwann cells, the ensheathing glial cells of the peripheral nerve system, are crucial for normal nerve function and for nerve repair.…”

“…For the purpose of tracking endogenous SCs in penis, all SD rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) at postnatal day one by using label-retaining cells (LRC) strategy Xu et al, 2015). Twelve weeks later, CN exposure with or without injury was performed as previously described (Bella et al, 2007).…”

Maintenance of the contractile phenotype in corpus cavernosum smooth muscle cells by Myocardin gene therapy ameliorates erectile dysfunction in bilateral cavernous nerve injury rats

“…In recent years, several studies have highlighted the therapeutic potential of, and the underlying mechanism for, the involvement of endogenous stem cells (SCs) in these two treatments. Rats that underwent injection of EdU for the purpose of tracking endogenous SCs at birth and management of BCNI or pelvic neurovascular injury at 12 weeks were treated with the antioxidant agent icariside II (Xu et al ., ) or Li‐ESWT (Li et al ., ). Both the studies reported erectile dysfunction improvement, tissue restoration and more endogenous EdU (+) SCs recruited to the damaged penile areas, implying the probability of self‐healing by endogenous SC mobilization and activation.…”

Current Perspectives on Stem Cell Therapy for Erectile Dysfunction

“…Xu et al activated the p38 mitogen-activated protein kinase (MAPK) pathway to stimulate endogenous stem cells. 60 The p38 MAPK pathway is thought to be integral in stem cell activation and differentiation and as such may serve alongside LESWT as another means of activating these endogenous cells.…”