Abstract
The present study was aimed to examine whether icariin, a traditional Chinese medicine, could improve therapeutic effects of adipose derived mesenchymal stem cells (ADSCs) for diabetes-associated erectile dysfunction (DMED). DMED were induced in rats by intraperitoneal injection of streptozotocin and confirmed by erectile function measurement. Then, rats of diabetic ED were randomly divided to receive the treatment of saline, ADSCs, icariin or ADSCs combined with icariin respectively. Compared with the treatment by ADSCs or icariin alone, intracavernosum injection of ADSCs combined with the following daily gastric gavage of icariin significantly augmented the value of ICP and ICP/MAP (p<0.01). Meanwhile, the survival of transplanted ADSCs was much improved due to the application of icariin. Similarly, immunofluorescent staining analysis demonstrated that the improved erectile tissue structure by combination of ADSCs and icariin was significantly associated with the increased expression of endothelial markers (vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Furthermore, the structure changes in corpus cavernosum were further confirmed by the Masson’s trichrome staining. To explore the possible mechanism underlying icariin-enhanced therapeutic efficacy of MSCs, we employed an in vitro testing system by introducing H2O2 to imitate oxidative stress condition considering the oxidative environment faced by engrafted ADSCs and anti-oxidative capacity of icariin. In vitro, we found that the addition of icariin considerably reduced the apoptosis of ADSCs, and attenuated the intracellular reactive oxygen species (ROS), the superoxidase dismutase (SOD) activity and the lactate dehydrogenase (LDH). Subsequently, we examined the expression of apoptosis-related proteins and explored the potential signaling pathway through which icariin promoted the survival of ADSCs against oxidative stress. It was demonstrated that icariin significantly inhibited the upregulation of apoptosis-related proteins under oxidative condition, including Bax and cleaved caspase-3, while promoted the expression of anti-apoptotic factor BCL2. These effects were accompanied with the activation of signal molecules, PI3K/Akt and STAT3. The further signal protein inhibition assays exhibited that the suppression of STAT3 abrogated the icariin-mediated anti-apoptotic effects observed above, while did not influence the expression of PI3K/Akt. However, PI3K inhibition could abrogate icariin–mediated STAT3 activation and achieved a similar effect as STAT3 inhibition. Our results suggested that icariin was an effective adjuvant for enhancing ADSC-based therapy of DMEM, which may be ascribed to their protection of ADSCs against oxidative stress via the regulation of PI3K/Akt-STAT3 signal pathway.
Highlights
Erectile dysfunction (ED), otherwise known as impotency in men, has an impact on over 30 million men every year, threatening human health and life
Our results suggested that icariin was an effective adjuvant for enhancing adipose derived mesenchymal stem cells (ADSCs)-based therapy of DMEM, which may be ascribed to their protection of ADSCs against oxidative stress via the regulation of PI3K/Akt-STAT3 signal pathway
In vivo survival of ADSCs and diabetic erectile function assessment To track the survival of transplanted cells, ADSCs were labeled with DiI pre-transplantation and one week post transplantation, the survival of transplanted ADSCs were detected by observation with fluorescent microscope
Summary
Erectile dysfunction (ED), otherwise known as impotency in men, has an impact on over 30 million men every year, threatening human health and life. Various risk factors contribute to the incidence of ED among which diabetes mellitus (DM) is showed to be highly associated. Functional impairments in blood vessel, muscle, and nerve [3] possess the main responsibility. DM was able to produce oxidative stress damage in cavernoursal tissues, usually resulting in the loss of the physiological properties of endothelium and shifting to a vasoconstrictor, pro-thrombotic and pro-inflammatory state [4, 5], which is considered to be crucial in the early development of diabetic-associated erectile dysfunction (DMED). Cavernoursal smooth muscles are found to lose their function in DMED, along with the reduction of low density lipoprotein (LDL) and the augment of reactive oxygen species (ROS) [6]
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