Abstract
BackgroundIn our previous research, we found that mesenchymal stem cell (MSC) transplantation therapy can inhibit intimal hyperplasia and enhance endothelial function in arterialized vein grafts in rats. However, whether MSC-derived exosomes (MSC-exosomes) can reduce neointimal formation and its possible mechanism is still unclear.MethodsThe primary human umbilical cord MSCs (hucMSCs) and human umbilical vein endothelial cells (HUVECs) were isolated and characterized by flow cytometry and immunofluorescence. The exosomes derived from hucMSCs (hucMSC-exosomes) were identified by transmission electron microscopy and western blots. hucMSC-exosomes were intravenously injected into a rat model of vein grafting, and its effect on vein grafts reendothelialization and intimal hyperplasia was assessed by physical, histological, immunohistochemistry, and immunofluorescence examinations. The effects of hucMSC-exosomes on endothelial cells were evaluated by integrated experiment, EdU staining, scratch assay, and Transwell assay. The expression levels of key gene and pathways associated with the biological activity of vascular endothelial cells were evaluated following the stimulation of hucMSC-exosomes.ResultsWe successfully isolated and characterized primary hucMSCs and hucMSC-exosomes and primary HUVECs. We verified that the systemic administration of hucMSC-exosomes accelerates reendothelialization and decreases intimal hyperplasia of autologous vein graft in a rat model. We also identified that hucMSC-exosomes can be uptaken by endothelial cells to stimulate cell proliferative and migratory activity in vitro. Furthermore, we detected that vascular endothelial growth factor (VEGF) plays an important part in hucMSC-exosome-mediated proliferation and migration in HUVECs. In addition, we also provided evidence that the signalling pathways of PI3K/AKT and MAPK/ERK1/2 take part in hucMSC-exosome-induced VEGF regulation.ConclusionOur data suggest that hucMSC-exosomes exert a vasculoprotective role in the setting of vein graft disease, which may provide a new clue to protect against vein graft failure in the future.
Highlights
In our previous research, we found that mesenchymal stem cell (MSC) transplantation therapy can inhibit intimal hyperplasia and enhance endothelial function in arterialized vein grafts in rats
The potential of adipogenic differentiation and chondrogenic differentiation of human umbilical cord MSCs (hucMSCs) were confirmed by Alcian blue staining and Oil Red O staining after 2–3 weeks of differentiation (Fig. 1c, d)
Because matrix metalloproteinases (MMPs) are important agents in promoting Smooth muscle cell (SMC) migration and subsequent extracellular matrix deposition (ECM) in neointima [21], we evaluated the expression of MMP-2 and MMP-9 in grafted veins by immunohistochemistry
Summary
We found that mesenchymal stem cell (MSC) transplantation therapy can inhibit intimal hyperplasia and enhance endothelial function in arterialized vein grafts in rats. Coronary artery bypass graft surgery (CABG) with autogenous vein is the most widely used and recommended therapies for severe ischaemic heart disease [1]. There is accumulating evidence suggesting that beneficial effects of stem cell transplantation might be largely, or at least partially, caused by a paracrine mechanism [4, 5]. Small membrane vesicles secreted from many kinds of cells, are an important part of paracrine secretion. They are positive for CD9, CD63, and CD81. Non-cell-based MSC-exosome therapy decreases numerous complications related to cellular transplantation, such as immune reaction, malignant proliferation, and vascular embolization [4]
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