Hydrogen Sulfide-Preconditioning of Human Endothelial Progenitor Cells Transplantation Improves Re-Endothelialization in Nude Mice with Carotid Artery Injury

Abstract

Background/Aims: The aim of present study was to test the hypothesis that preconditioning with sodium hydrosulfide (NaHS) could enhance the capacity of migration, adhesion and proliferation of endothelial progenitor cells (EPCs) in vitro, and also could improve the efficacy of EPCs transplantation for re-endothelialization in nude mice with carotid artery injury. The paper further addressed the underlying mechanisms. Methods: EPCs were isolated from peripheral blood mononuclear cells of healthy male volunteers and the markers of EPCs were analyzed by flow cytometry. Thereafter, different concentrations of NaHS (25, 50, 100, 200 and 500 uM) were used for preconditioning EPCs. In vitro and in vivo migration, adhesion and proliferation as well as nitric oxide (NO) production of EPCs were evaluated. Carotid artery injury model was produced in nude mice and thereafter, NaHS-preconditioned EPCs were transplanted in order to evaluate their capacity of re-endothelialization. Results: Cellular immuno-staining showed that isolated cells expressed the key markers of EPCs. In vitro, EPCs proliferation rates and NO production were gradually increased in a NaHS-concentration dependent manner, while these benefits were blocked at a concentration of 500 uM NaHS. Similarly, the migration and adhesion rates of EPCs were also increased the most prominently at a concentration of 200 µM NaHS. In vivo, compared to the control group, treatment with NaHS-preconditioned EPCs significantly enhanced the capacity of re-endothelialization of EPCs. Fluorescent microscope revealed that there were more EPCs homing to the injury vessels in the NaHS-preconditioned EPCs group than the non-preconditioned group. With the administration of AMPK or eNOS inhibitors respectively, the above benefits of NaHS-preconditioning were abrogated. Conclusion: These results suggested that NaHS-preconditioning enhanced the biological function and re-endothelialization of EPCs through the AMPK/eNOS signaling pathway.

Glutathione–Allylsulfur Conjugates as Mesenchymal Stem Cells Stimulating Agents for Potential Applications in Tissue Repair

“…These results are in agreement with the recent studies that demonstrate that H 2 S is able to promote migration and wound healing. The underlying mechanism involves increased levels of p-Akt, p-ERK1/2 and phosphorylated glycogen synthase kinase-3b [81][82][83]. Overall these results demonstrate that prolonged cell GSGa pre-conditioning could represent a powerful tool for selecting adult stem-cell lines that maintain an increased proliferative and migration capability and resistance to oxidative stress, suggesting a potential successful approach for future in vivo/therapeutic applications.…”

“…Thus, the therapeutic efficacy of cardiac progenitor/stem cell transplantation could be enhanced by the overexpression of Cx43 because it promotes neovascularization, reduces infarct size and preserves cardiac function preservation in the ischemic heart [80][81][82]. Cell therapy using MSC overexpressing Cx43 reduces infarct size, improving the heart functionality [74,80].…”

“…Currently, not many studies have investigated the use of H 2 S-donors in tissue repair, and most of them are focused on short-term preconditioning of the stem cells prior to transplantation. The time-span of the pretreatment varies from as short as 30 min to 48-72 h [45,81,82]. A selected cell line named GcMSC was obtained after long-term preconditioning and was here characterized.…”

The effect of endothelial progenitor cell transplantation on neointimal hyperplasia and reendothelialisation after balloon catheter injury in rat carotid arteries

“…Hagensen et al suggested that the migration of adjacent arterial endothelial cells is the only source of reendothelialisation [11,12]. However, other studies have stated that transplanting EPCs not only promoted reendothelialisation through the paracrine function, but also differentiated into mature ECs [10,45,46]. Transplanted EPCs labelled with PKH26 were attached to the injured luminal surface on the first day after BI.…”

Hydrogen Sulfide in Bone Tissue Regeneration and Repair: State of the Art and New Perspectives

“…H 2 S has been found to induce migratory properties in both cell types. In particular, NaHS, an H 2 S donor, increases the mobilization of EPCs after vascular injury, enhancing their adhesion and colony formation capacities [61] and improving re-endothelization in nude mice with carotid artery injury [62]. CSE-mediated H 2 S deficiency in high glucose-treated MSCs impairs their migratory capacity, which was further restored by NaHS treatments [63].…”