Zheyong Huang

Impact of Timing on Efficacy and Safetyof Intracoronary Autologous Bone Marrow Stem Cells Transplantation in Acute Myocardial Infarction: A Pooled Subgroup Analysis of Randomized Controlled Trials

Until now there were no clinical studies or systematic reviews to investigate the impact of timing on efficacy and safety of intracoronary bone marrow stem cell (BMSC) transfer in patients with acute myocardial infarction (AMI).

Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: a meta-analysis of randomised controlled trials.

BACKGROUND Conflicting results existed now on the clinical utility of intracoronary bone marrow stem cells (BMSC) transfer for acute myocardial infarction (AMI). This study sought to analyze the efficacy and safety of autologous BMSC transfer in patients with AMI by performing a meta-analysis based on published randomised controlled trials. METHODS A systematic literature search of PubMed, MEDLINE, BIOSIS, EMBASE, and Cochrane EBM databases during the period of 1990-2007 was made, objective being the randomised controlled trials in patients with AMI who underwent primary percutaneous coronary intervention (PCI) and received intracoronary BMSC transfer, and were followed up for at least 3 months. RESULTS A total of 6 trials with 525 patients were available for analysis. The pooled statistics showed the mean increase in left ventricular ejection fraction (LVEF) from baseline was 7.05% in BMSC group (p=0.01), whereas only 2.46% in control group (p=0.02), and the effect on the absolute change in LVEF was an increase of 4.77% compared with the control (95% confidence interval [CI] 1.42% to 8.12%; p=0.005). The similar effect on left ventricular (LV) end-diastolic dimensions was demonstrated in inter-group comparison (standardized mean difference [SMD]=-0.15, 95%CI -0.50 to 0.20; p=0.41). The incidence of major adverse cardiac events was also similar in two groups but in favor of BMSC group (relative risk [RR]=0.85, 95%CI, 0.61 to 1.19; p=0.34). CONCLUSIONS Post PCI BMSC transplantation in patients with AMI significantly increases LVEF but has no effects on LV remodeling, and there is not an incremental effect on the occurrence of major adverse cardiac events in the observed period.

Deep magnetic capture of magnetically loaded cells for spatially targeted therapeutics

Magnetic targeting has recently demonstrated potential in promoting magnetically loaded cell delivery to target lesion, but its application is limited by magnetic attenuation. For deep magnetic capture of cells for spatial targeting therapeutics, we designed a magnetic pole, in which the magnetic field density can be focused at a distance from the pole. As flowing through a tube served as a model of blood vessels, the magnetically loaded mesenchymal stem cells (MagMSCs) were highly enriched at the site distance from the magnetic pole. The cell capture efficiency was positively influenced by the magnetic flux density, and inversely influenced by the flow velocity, and well-fitted with the deductive value by theoretical considerations. It appeared to us that the spatially-focused property of the magnetic apparatus promises a new deep targeting strategy to promote homing and engraftment for cellular therapy.

High density lipoprotein protects mesenchymal stem cells from oxidative stress-induced apoptosis via activation of the PI3K/Akt pathway and suppression of reactive oxygen species.

The therapeutic effect of transplantation of mesenchymal stem cells (MSCs) in myocardial infarction (MI) appears to be limited by poor cell viability in the injured tissue, which is a consequence of oxidative stress and pro-apoptotic factors. High density lipoprotein (HDL) reverses cholesterol transport and has anti-oxidative and anti-apoptotic properties. We, therefore, investigated whether HDL could protect MSCs from oxidative stress-induced apoptosis. MSCs derived from the bone marrow of rats were pre-incubated with or without HDL, and then were exposed to hydrogen peroxide (H2O2) in vitro, or were transplanted into experimentally infarcted hearts of rats in vivo. Pre-incubation of MSCs with HDL increased cell viability, reduced apoptotic indices and resulted in parallel decreases in reactive oxygen species (ROS) in comparison with control MSCs. Each of the beneficial effects of HDL on MSCs was attenuated by inhibiting the PI3K/Akt pathway. Preconditioning with HDL resulted in higher MSC survival rates, improved cardiac remodeling and better myocardial function than in the MSC control group. Collectively, these results suggest that HDL may protect against H2O2-induced apoptosis in MSCs through activation of a PI3K/Akt pathway, and by suppressing the production of ROS.

Synthetic ePTFE grafts coated with an anti-CD133 antibody-functionalized heparin/collagen multilayer with rapid in vivo endothelialization properties.

An anti-CD133 antibody multilayer functionalized by heparin/collagen on an expanded polytetrafluoroethylene (ePTFE) graft was developed to accelerate early endothelialization. The surface modification of ePTFE grafts demonstrated that the multilayer is stable in static incubation and shaking conditions and that the anti-CD133 antibodies were successfully cross-linked onto the surface. Blood compatibility tests revealed that the coimmobilized heparin/collagen films in the presence or absence of anti-CD133 antibodies prolonged the blood coagulation time and that there was less platelet activation and aggregation, whereas the hemolysis rate was comparable with the bare ePTFE grafts. Cellular proliferation was not inhibited, as the heparin/collagen synthetic vascular grafts coated with CD133 antibody showed little cytotoxicity. The endothelial cells adhered well to the modified ePTFE grafts during a cell adhesion assay. A porcine carotid artery transplantation model was used to evaluate the modified ePTFE grafts in vivo. The results of histopathological staining and scanning electron microscopy indicated that the anti-CD133 antibody was able to accelerate the attachment of vascular endothelial cells onto the ePTFE grafts, resulting in early rapid endothelialization. The success of the anti-CD133 antibody-functionalized heparin/collagen multilayer will provide an effective selection system for the surface modification of synthetic vascular grafts and improve their use in clinical applications.

Myocardial transfection of hypoxia-inducible factor-1α and co-transplantation of mesenchymal stem cells enhance cardiac repair in rats with experimental myocardial infarction

IntroductionMesenchymal stem cells (MSCs) have potential for the treatment of myocardial infarction. However, several meta-analyses revealed that the outcome of stem cell transplantation is dissatisfactory. A series of studies demonstrated that the combination of cell and gene therapy was a promising strategy to enhance therapeutic efficiency. The aim of this research is to investigate whether and how the combination of overexpression of hypoxia-inducible factor-1α (HIF-1α) and co-transplantation of mesenchymal stem cells can enhance cardiac repair in myocardial infarction.MethodsWe investigated the therapeutic effects of myocardial transfection of HIF-1α and co-transplantation of MSCs on cardiac repair in myocardial infarction by using myocardial transfection of HIF-1α via an adenoviral vector. Myocardial infarction was produced by coronary ligation in Sprague-Dawley (SD) rats. Animals were divided randomly into six groups: (1) HIF-1α + MSCs group: Ad-HIF-1α (6 × 109 plate forming unit) and MSCs (1 × 106) were intramyocardially injected into the border zone simultaneously; (2) HIF-1α group: Ad-HIF-1α (6 × 109 plate forming unit) was injected into the border zone; (3) HIF-1α-MSCs group: Ad-HIF-1α transfected MSCs (1 × 106) were injected into the border zone; (4) MSCs group: MSCs (1 × 106) were injected into the border zone; (5) Control group: same volume of DMEM was injected; (6) SHAM group. Cardiac performance was then quantified by echocardiography as well as molecular and pathologic analysis of heart samples in the peri-infarcted region and the infarcted region at serial time points. The survival and engraftment of transplanted MSCs were also assessed.ResultsMyocardial transfection of HIF-1α combined with MSC transplantation in the peri-infarcted region improved cardiac function four weeks after myocardial infarction. Significant increases in vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) expression, angiogenesis and MSC engraftment, as well as decreased cardiomyocyte apoptosis in peri-infarcted regions in the hearts of the HIF-1α + MSCs group were detected compared to the MSCs group and Control group.ConclusionsThese findings suggest that myocardial transfection of HIF-1α and co-transplantation of mesenchymal stem cells enhance cardiac repair in myocardial infarction, indicating the feasibility and preliminary safety of a combination of myocardial transfection of HIF-1α and MSC transplantation to treat myocardial infarction.

Magnetic targeting enhances retrograde cell retention in a rat model of myocardial infarction

IntroductionRetrograde coronary venous infusion is a promising delivery method for cellular cardiomyoplasty. Poor cell retention is the major obstacle to the establishment of this method as the preferred route for cell delivery. Here, we explored whether magnetic targeting could enhance retrograde cell retention in a rat model of myocardial infarction.MethodsRat mesenchymal stem cells were labeled with superparamagnetic oxide nanoparticles. The magnetic responsiveness of MSCs was observed while cells flowed through a tube that served as a model of blood vessels in a 0.6-Tesla magnetic field. In a Sprague–Dawley rat model of acute myocardial infarction, 1 × 106 magnetic mesenchymal stem cells were transjugularly injected into the left cardiac vein while a 0.6-Tesla magnet was placed above the heart. The cardiac retention of transplanted cells was assessed by using quantitative Y chromosome-specific polymerase chain reaction, cardiac magnetic resonance imaging, and optical imaging. Cardiac function was measured by using echocardiography, and histologic analyses of infarct morphology and angiogenesis were obtained.ResultsThe flowing iron oxide-labeled mesenchymal stem cells were effectively attracted to the area where the magnet was positioned. Twenty-four hours after cellular retrocoronary delivery, magnetic targeting significantly increased the cardiac retention of transplanted cells by 2.73- to 2.87-fold. Histologic analyses showed that more transplanted cells were distributed in the anterior wall of the left ventricle. The enhanced cell engraftment persisted for at least 3 weeks, at which time, left ventricular remodeling was attenuated, and cardiac function benefit was improved.ConclusionsThese results suggest that magnetic targeting offers new perspectives for retrograde coronary venous delivery to enhance cell retention and subsequent functional benefit in heart diseases.

Host Vascular Niche Contributes to Myocardial Repair Induced by Intracoronary Transplantation of Bone Marrow CD34+ Progenitor Cells in Infarcted Swine Heart

The effects of bone marrow cell transplantation (BMT) on myocardial infarct might be affected by host intrinsic circumferences. A best vascular niche was shown in the infarcted hearts with collateral vessels at 2 weeks after myocardial infarction (MI). BMT caused the greatest cardiac repairs after MI in the swine with better collateral vessels, which might be relative to richer collateral vessels, greater vessel densities, and higher expressions of basif fibroblast growth factor and stromal cell–derived factor‐1 in the hearts before BMT. Our data suggest that existence of intrinsic collateral vessels contributes greatly to the beneficial effects of intracoronary BMT on cardiac repairs after MI.

High density lipoprotein cholesterol promotes the proliferation of bone-derived mesenchymal stem cells via binding scavenger receptor-B type I and activation of PI3K/Akt, MAPK/ERK1/2 pathways

High-density lipoprotein (HDL) possesses protective properties in cardiovascular diseases. However, the effect of HDL on the mesenchymal stem cells (MSCs), which could be mobilized to the damaged myocardial tissue, has not been well elucidated yet. In the current study, we investigated the effect of HDL on the proliferation of MSCs so as to reveal its molecular mechanisms. MSCs derived from rats were treated with HDL in different concentrations and for different periods. The proliferation of MSCs was measured with MTT and BrdU cell proliferation assay. The phosphorylation of Akt, ERK1/2 and the expression of p21 were evaluated by Western blotting. After the activity of respective pathways was down-regulated by the specific inhibitor and the gene of scavenger receptor-B type I (SR-BI) was knocked down by RNA interference, BrdU assay was performed to examine this effect of HDL on MSCs. We found that the proliferation of MSCs induced by HDL, in a time- and concentration-dependent manner, was the phosphorylation of Akt- and ERK1/2-dependent, which was significantly attenuated by the specific inhibitor to respective pathways. Moreover, MAPK/ERK1/2 pathway exerted a more dominating effect on this process. SR-BI contributed to HDL-induced proliferation of MSCs, which was effectively abolished by the silencing of SR-BI. The results suggested that HDL was capable of improving MSCs proliferation, in which MAPK/ERK1/2 and PI3K/Akt pathways involved and SR-BI played a critical role as well.

miR-210 over-expression enhances mesenchymal stem cell survival in an oxidative stress environment through antioxidation and c-Met pathway activation

AbstractmicroRNA-210 (miR-210) has generally been reported to be associated with cell survival under hypoxia. However, there are few data regarding the role of miR-210 in the survival of mesenchymal stem cells (MSCs) under oxidative stress conditions. Thus, we sought to investigate whether miR-210 over-expression could protect MSCs against oxidative stress injury and what the primary mechanisms involved are. The results showed that over-expression of miR-210 significantly reduced the apoptosis of MSCs under oxidative stress, accompanied by obvious increases in cell viability and superoxide dismutase activity and remarkable decreases in malonaldehyde content and reactive oxygen species production, resulting in a noticeable reduction of apoptotic indices when compared with the control. Moreover, the above beneficial effects of miR-210 could be significantly reduced by c-Met pathway repression. Collectively, these results showed that miR-210 over-expression improved MSC survival under oxidative stress through antioxidation and c-Met pathway activation, indicating the potential development of a novel approach to enhance the efficacy of MSC-based therapy for injured myocardium.