Abstract
BackgroundThe transplantation of bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutic strategy for wound healing. However, the poor migration capacity and low survival rate of transplanted BMSCs in wounds weaken their potential application.ObjectiveTo identify the optimal protocol for BMSCs preconditioned with H2O2 and improve the therapeutic efficacy using H2O2-preconditioned BMSCs in wound healing.MethodsMouse BMSCs were exposed to various concentrations of H2O2, and the key cellular functional properties were assessed to determine the optimal precondition with H2O2. The H2O2-preconditioned BMSCs were transplanted into mice with full-thickness excisional wounds to evaluate their healing capacity and tissue engraftment.ResultsTreatment BMSCs with 50 μM H2O2 for 12 h could significantly enhance their proliferation, migration, and survival by maximizing the upregulation of cyclin D1, SDF-1, and its receptors CXCR4/7 expressions, and activating the PI3K/Akt/mTOR pathway, but inhibiting the expression of p16 and GSK-3β. Meanwhile, oxidative stress-induced BMSC apoptosis was also significantly attenuated by the same protocol pretreatment with a decreased ratio of Bax/Bcl-2 and cleaved caspase-9/3 expression. Moreover, after the identification of the optimal protocol of H2O2 precondition in vitro, the migration and tissue engraftment of transfused BMSCs with H2O2 preconditioning were dramatically increased into the wound site as compared to the un-preconditioned BMSCs. The increased microvessel density and the speedy closure of the wounds were observed after the transfusion of H2O2-preconditioned BMSCs.ConclusionsThe findings suggested that 50 μM H2O2 pretreated for 12 h is the optimal precondition for the transplantation of BMSCs, which gives a considerable insight that this protocol may be served as a promising candidate for improving the therapeutic potential of BMSCs for wound healing.
Highlights
Growing evidence indicates that bone marrow mesenchymal stem cells (BMSCs)-based therapy for cutaneous wound healing holds great therapeutic value via differentiating into specialized cell types, producing a large variety of growth factors, and promoting wound closure and angiogenesis [1,2,3,4]
Treatment of BMSCs with 50 μM Hydrogen peroxide (H2O2) significantly enhanced cell viability, proliferation, and migration by augmenting the Stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4)/CXCR7 axis To define the optimal concentration of H2O2 in preconditioning BMSCs, we selected five different concentrations between 25 and 200 μM based on previous reports [29] and investigated its effects on cellular properties of viability, proliferation, migration, and differentiation
By using the ATP assay and CCK-8 assay, we found that H2O2 at 25 μM and 50 μM significantly increased the viability of BMSCs (Fig. 1a) and promoted the proliferation of BMSCs (Fig. 1b), accompanied by an increase in cyclin D1 expression and decrease in p16 expression, whereas 150 and 200 μM H2O2 showed a significant inhibitory effect compared with that of the control
Summary
Growing evidence indicates that BMSC-based therapy for cutaneous wound healing holds great therapeutic value via differentiating into specialized cell types, producing a large variety of growth factors, and promoting wound closure and angiogenesis [1,2,3,4]. Transplantation of BMSCs is a promising therapeutic strategy for wound healing [1]. During in vitro culture expansion, BMSCs lose their CXCR4 receptor [9] and reduce their binding capacity to SDF-1 resulting in [10, 11] attenuation of their migration capacity. Various stress conditions including ex vivo isolation, in vitro expansion of MSCs, and confronting the harsh microenvironment (ischemia, hypoxia, and inflammation) caused oxidative stress injury to BMSCs following engraftment at injured sites, resulting in reducing survival of transplanted BMSCs [12,13,14]. The transplantation of bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutic strategy for wound healing. The poor migration capacity and low survival rate of transplanted BMSCs in wounds weaken their potential application
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