Abstract
Denervation-induced erectile dysfunction (ED) is a prevailing health problem. Our previous study revealed that endothelial progenitor cells (EPCs) promoted the effect of mesenchymal stem cells (MSCs) on restoration of denervation-induced ED in rats. However, underling mechanisms are still largely elusive. In this study, EPCs and MSCs were co-cultured and resorted to co-EPCs and co-MSCs. EPCs-derived paracrine factors containing PDGF-BB (platelet-derived growth factor) were detected, and MSCs were pre-treated with PDGF-BB, while co-MSCs were pre-treated with PDGFR inhibitor AG1296. Either viability or nerve regenerative ability of MSCs was evaluated. In addition, inhibition of either PI3K/Akt or MEK/Erk pathway was performed to evaluate the role of PI3K/Akt and MEK/Erk pathway in PDGF-BB-induced viability of MSCs. The results revealed that PDGF-BB significantly increased the proportion of PDGFR-β+ MSCs, and promoted both in-vitro and in-vivo viability, as well as nerve regenerative capacity and erectile function restoration of MSCs in rats. Inhibition of PI3K/Akt, MEK/Erk pathway or mTOR led to decrease of PDGF-BB/PDGFR-β induced viability of MSCs. To our knowledge, our study first demonstrates that EPCs promote viability and potential nerve regenerative ability of MSCs through PDGF-BB/PDGFR-β signaling and its downstream PI3K/Akt and MEK/Erk pathways. mTOR acts as a co-mediator in PI3K/Akt and MEK/Erk pathways.
Highlights
Due to intraoperative damage of pelvic autonomic nerve, erectile dysfunction (ED) frequently occurs after pelvic surgery [1, 2]
To determine the role of PI3K/Akt and MEK/Erk pathway in PDGF-BB-induced viability of mesenchymal stem cells (MSCs), MSCs treated with PDGF-BB were pre-treated with PI3K inhibitor LY294002, Erk inhibitor PD98059 or mTOR inhibitor rapamycin, respectively
endothelial progenitor cells (EPCs) have been proved to participate in angiogenesis and microvascular neovascularization, as well as serve as a trophic mediator for MSCs engraftment via paracrine signaling
Summary
Due to intraoperative damage of pelvic autonomic nerve, erectile dysfunction (ED) frequently occurs after pelvic surgery [1, 2]. Previous studies have documented that the adoptive transfer of mesenchymal stem cells (MSCs) is effective for ED in animals [4, 5]. Our previous study proved that periprostatic implantation of neuronal differentiated MSCs was effective on ameliorating erectile function in rats. The mechanism may be ascribed to both decrease of apoptotic cells and paracrine effect of MSCs [6]. A clinical trial of stem cell therapy for ED revealed that despite having increased penile rigidity, none of the 7 diabetic related ED patients was able to achieve vaginal penetration [7]. The lack of efficacy www.aging-us.com could be ascribed to multiple factors, containing insufficient understanding of pharmacokinetics of the administered cells. More efficient studies on the use of MSCs therapy are in need to restore erectile function better
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