| Background:The endothelium not only forms a selective barrier between the vessel lumen and surrounding tissue but also takes part in many aspects of vascular biology. including vasoconstriction,vasodilation,blood clotting,atherosclerosis,angiogenesis and inflammation.Endothelial dysfunction is one important pathophysiological step of atherosclerosis and restenosis after angioplasty.Stem cells hold a great potential for the regeneration of damaged tissues in cardiovascular diseases.The advancement of stem cell technology brings about prospectives in the treatment of endothelium dysfunction. Mesenchymal stem cells(MSCs) are one of stem cell types undergoing extensive investigation for cell-based therapeutic strategies.Aims:In the present study,we investigated the effect of MSC delivery on the regeneration of endothelium and recovery of endothelial function in denudated carotids.Methods:Allogeneic MSCs were obtained from rabbit bone marrow(BM) aspirates. MSCs of passage 3 were labeled with CM-DiI and used in the experiment.A rabbit model of common carotid artery denudation by passage of an inflated balloon catheter was used.New Zealand White rabbits were randomly divided into three groups:rabbits receiving administration of either 10~5 MSCs(n=22) or saline(n=22) into the lumen of injured artery immediately after balloon angioplasty and additional rabbits(n=4) were served as controls.We extracted total RNA from injured and contralateral uninjured carotids harvested at 3 and 7 days after balloon angioplasty from MSC-(n=5 for each time point) or saline-treated rabbits(n=5 for each time point).Real-time reverse transcription-polymerase chain reaction(RT-PCR) was performed to validate the expression of inflammation-related gene,including interleukin-6(IL-6),interleukin-10 (IL-10),transforming growth factor beta(TGF-β),interferon-gamma(IFN-γ),and tumor necrosis factor-alpha(TNF-α).Four weeks after balloon angioplasty.carotid arteries were harvested for vasodilatory function analysis and histological analysis.Results:Four weeks after transplant,fluorescence-labeled colonies of MSCs were found in the injured vessel wall of MSC-treated carotids.Local transfer of allogeneic MSCs as compared with saline administration caused enhanced reendothelialization and reduced neointima formation when assessed 4 weeks after denudation(p＜0.05).MSC delivery improved endothelium-dependent vasorelaxation at 4 weeks compared with saline(p＜0.01).Moreover,MSC treatment affected the expression level of inflammation-related genes,inducing an increase of TGF-βin injured carotids at 3 and 7 days after angioplasty and a decrease of IL-6 in injured carotids at 3 days after angioplasty(p＜0.05).Conclusions:Taken together,these data indicate that local delivery of allogeneic MSCs played a local immunomodulatory action,caused an increased reendothelialization and endothelium-dependent vasorelaxation as well as a markedly reduced neointima formation in rabbit model of common carotid artery denudation.These results bring new insights into MSC biology and the treatment of vascular dysfunction and prevention of restenosis after angioplasty. Background:Atherosclerosis,the primary cause of heart disease and stroke,is a multifactorial process with complicated aetiology.It is considered as a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis.Thrombo-occlusive complications of atherosclerosis,including stroke and myocardial infarction,are becoming major causes of morbidity and mortality in the industrialized world.Epidemiological studies have revealed several important environmental and genetic risk factors associated with atherosclerosis,such as elevated levels of homocysteine,hyperlipidemia,hypertension,diabetes,smoking,lack of exercises,family history etc.Mesenchymal stem cells(MSC) are present in adult tissues,including bone marrow and adipose,from which they can be easily isolated and cultured ex vivo.Recent experimental observations indicate that MSCs are capable of differentiating into endothelial cells,facilitate both myocardial repair and neovascularization in models of cardiac injury.But the safety of MSC transplantation in the setting of atherosclerosis has not yet been demonstrated.Aims:The present study was designed to evaluate the safety and the effects of MSC-based therapy in the setting of atherosclerosis.Methods:Allogeneic MSCs were obtained from rabbit bone marrow aspirates and expanded in vitro.New Zealand White rabbits were divided into three groups:24 rabbits with hypercholesterolemia receiving intravenous injection of either 1.15×10~7/kg MSCs (n=12) or saline(n=12) after 5 weeks on a high lipid diet and additional rabbits(n=6) fed with standard rabbit diet were served as controls.Body weight and blood lipids were measured at weeks 0.5,9 and 13 during the study.All rabbits were euthanized at week 13.Atherosclerotic plaque size,atherosclerotic plaque composition and vasa vasorum were evaluated using pathological analysis and immunocytochemical technique.Results:Aortic sinus lesion size was significantly increased in rabbits receiving MSCs compared with saline controls(23.35±3.51%and 11.39±3.08%respectively).The lesion size in whole aortas of MSC-treated rabbits was 76.64±12.70%versus 57.61±9.00%in saline-treated animals(p＜0.05).Moreover.Vasa vasorum networks in MSC-treated aortas are more numerous and have increased capillary density.Conclusions:We demonstrated for the first time that allogeneic MSC transfer may result in an increase in atherosclerotic lesion size.Cell therapy with MSCs or cell populations containing MSCs requires a strategy to attenuate the high potential of MSCs to contribute to atherogenesis in the context of atherosclerosis.
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