[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD(+)-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence. Aging-related proteins, P16 and P21 may be downstream effectors of the SIRT1-mediated anti-aging effects. SIRT1 protected MSCs from age-related DNA damage, induced telomerase reverse transcriptase (TERT) expression and enhanced telomerase activity but did not affect telomere length. SIRT1 positively regulated the expression of tripeptidyl peptidase 1 (TPP1), a component of the shelterin pathway that protects chromosome ends from DNA damage. Together, the results demonstrate that SIRT1 quenches age-related MSCs senescence by mechanisms that include enhanced TPP1 expression, increased telomerase activity and reduced DNA damage.
Frontiers in Aging Neuroscience 01/2014; 6:103. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Previous studies demonstrated that biological aging exerts a negative effect on the therapeutic effects of mesenchymal stem cells (MSCs)-based therapy. Here, using a rat myocardial infarction (MI) model, we tested the hypothesis that SIRT1 may ameliorate the phenotype and improve the function of aged MSCs and hence enhance the efficacy of aged MSCs-based therapy.
Sixty female rats experienced left anterior descending coronary artery ligation and were randomly assigned to receiving intramyocardial injection of cell culture medium (DMEM group), SIRT1 overexpression vector treated-aged MSCs (SIRT1-aged MSC group) obtained from aged male SD rats or empty vector treated-aged MSCs (vector-aged MSC group). Another twenty sham operated rats underwent open-chest surgery without coronary ligation and any other intervention served as controls.
SIRT1-aged MSCs group exhibited enhanced blood vessel density in the border zone of MI hearts, which was associated with reduced cardiac remodeling, leading to an improved cardiac performance. Consistent with the in vivo data, our in vitro experiments also demonstrated that SIRT1 overexpression ameliorated aged MSCs senescent phenotype and recapitulated the pro-angiogenesis property of MSCs and conferred the anti-stress response capabilities, as indicated by increases in pro-angiogenic factors, angiopoietin 1 (Ang1) and basic fibroblast growth factor (bFGF), expressions and a decrease in anti-angiogenic factor thrombospondin-1 (TBS1) at mRNA levels, and increases in Bcl-2/Bax ratio at protein level.
Up-regulating SIRT1 expression could enhance the efficacy of aged MSCs-based therapy for MI which is related to the amelioration of senescent phenotype and hence improved biological function of aged MSCs.
The Journal of Heart and Lung Transplantation. 01/2014;
[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cell (MSC) transplantation has been known to decrease matrix metalloproteinase (MMP) synthesis in myocardium after myocardial infarction (MI) and improve ventricular remodeling; however, the underlying mechanisms are unclear. This study investigated the effects of MSC on MMP synthesis in cardiac fibroblasts (CFs) through paracrine actions. CFs were cultured under hypoxic (0.5% pO(2)) conditions for 24 h before co-culture with MSCs or hypoxia-preconditioned MSCs (H-MSCs) in transwell plates. CFs and MSCs/H-MSCs shared a medium with or without erythropoietin (EPO) neutralizing antibody (EPOAb) or EPO-soluble receptor (EPOsR). The results showed that protein expression and activity of MMP-2 and membrane type 1-MMP, but not MMP-9, in CFs were significantly increased in response to hypoxia and decreased after co-culture with MSCs or H-MSCs. Hypoxia up-regulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2 of CFs which was down-regulated after CFs' co-culture with MSCs. Tissue inhibitors of metalloproteinases-1 (TIMP-1) in CFs was decreased after hypoxia and increased when co-cultured with MSCs or H-MSCs. Exogenous EPOAb or EPOsR partially inhibited MSCs' effect on MMP-2 expression and activity in CFs. The present findings suggested that MSCs influence MMP/TIMP expression in CFs via the ERK1/2 pathway and EPO acts as a key factor in the paracrine actions of MSCs.
Experimental Biology and Medicine 08/2011; 236(10):1197-204. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The object of this study is to establish serum protein fingerprint models for early diagnosis and evaluation of luminal stenosis severity of CAD.
A total of 189 samples were analyzed by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) coupled with CM10 chips and bioinformatics tools.
Ten top-ranked proteins were selected as the potential fingerprints of pattern 1, which distinguishes patients with significant CAD (stenosis≥50%) from control individuals. Blind test was analyzed on the second day with a specificity of 79.3% and sensitivity of 78.3%. Pattern 2 distinguishes significant CAD from minimal CAD with luminal stenosis between 25% and 50%. The specificity and sensitivity of blind test for pattern 2 are 77.3% and 73.9%, respectively.
The SELDI-TOF MS technique combined with bioinformatics approaches may be a novel noninvasive method which can not only facilitate the discovery of diagnostic models for CAD and its severity, but also provide a useful tool for molecular diagnosis.
[Show abstract][Hide abstract] ABSTRACT: We hypothesized that anoxic preconditioning (AP) could enhance the cardioprotective effect of mesenchymal stem cells (MSCs).
Myocardial infarction (MI) was set up in Sprague-Dawley rats and left ventricles were randomly injected with the following: DMEM, MSCs and AP-MSCs. Cardiac function was assessed by echocardiography 4 weeks after transplantation, hematoxylin-eosin staining and Masson trichrome were performed subsequently.
Increased fractional shortening, ejection fraction and decreased infarct size were observed most obviously in AP-MSCs group, accompanied by increased arteriole density and cell survival.
AP enhanced the capacity of MSCs to repair infarcted myocardium, attributable to increased cell survival and angiogenesis.
International journal of cardiology 02/2008; 133(3):410-2. · 7.08 Impact Factor