Modulating endothelial adhesion and migration impacts stem cell therapies efficacy.

BACKGROUND: Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. METHODS: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. FINDINGS: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. INTERPRETATION: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. FUNDING: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health.

Stent-assisted embolization as "bailout" option in aortic aneurysm.

The authors report two cases of stent-assisted embolization (SAE) in the aorta. In one case, SAE was performed for treatment of a pseudoaneurysm; the procedure consisted of stent placement and embolization with an AMPLATZER Vascular Plug and detachable coils through the stent struts. In the second case, SAE was performed to stop acute bleeding from an aortoureteral fistula. Before SAE in this case, the aortic bifurcation was reconstructed with self-expandable and balloon-expandable stents. SAE was technically successful in both cases. SAE for aortic pathologic processes may be useful in selected cases as an alternative to surgery or endovascular stent-graft therapy.

In vitro comparison of the antiproliferative effects of rhenium-186 and rhenium-188 on human aortic endothelial cells.

PURPOSE: Rhenium-186 ((186)Re) and rhenium-188 ((188)Re) are promising radionuclides for the inhibition of restenosis after percutaneous transluminal angioplasty or other vascular interventions. Until now the maximal dose tolerance of endothelial cells has not been clearly known. MATERIALS AND METHODS: To characterize the effects of local irradiation treatment, human aortic endothelial cells (ECs) were incubated with different doses of (186)Re and (188)Re. Two days after plating, ECs received treatment for a period of 5 days. The total radiation doses applied were 1, 4, 8, 16, and 32 Gy. On days 1, 3, 5, 7, and 12 after initial rhenium incubation, cell growth, clonogenic activity, cell-cycle distribution, and cytoskeletal architecture were evaluated. RESULTS: From the first day on, a dose-dependent growth inhibition was observed. Cumulative doses of ≥32 Gy caused a weak colony formation and significant alterations in the cytoskeletal architecture. An increased fraction of cells in G2/M phase was seen for cumulative radiation doses of ≥16 Gy. Interestingly, there were no significant differences between (186)Re and (188)Re. CONCLUSION: Even for low dose rates of ß particles a dose-dependent proliferation inhibition of ECs is seen. Doses beyond 32 Gy alter the cytoskeletal architecture with possibly endothelial dysfunction and late thrombosis.

Endovascular treatment of venous graft stenosis in the inferior vena cava and the left hepatic vein after complex liver tumor resection.

Endovascular treatment has been reported for a variety of conditions that result in venous obstruction in the iliocaval territory. The present report describes a patient who underwent a complex resection of a tumor that infiltrated the retrohepatic segment of the inferior vena cava (IVC), necessitating replacement of the IVC with a polytetrafluoroethylene (PTFE) graft. Postoperatively, symptomatic venous obstruction occurred in the graft and the left hepatic vein. Treatment required stent placement bridging native veins and the graft. The patient underwent placement of a self-expanding stent within the IVC and the PTFE graft with treatment of the hepatic vein stenosis via jugular vein access.

Reduced thrombogenicity of nitinol stents--in vitro evaluation of different surface modifications and coatings.

The material and the surface patterns of intravascular stents play a pivotal role in activating platelets and triggering adherence of inflammatory cells that consecutively leads to renarrowing caused by neointimal hyperplasia. To improve these features, besides mechanical and chemical modifications, ways of masking the stent by covering have been developed. In addition, polymer-coated stents are used as vehicle for local drug delivery. But as substances used for this application are described to possess an inflammatory potential, this aspect has to be evaluated. In the present study we compared different approaches to surface alterations applied to a nitinol stent design. Besides commonly used techniques like passivation and electropolishing, we evaluated coatings with heparin, aluminium and a polyurethane polymer regarding their thrombogenic and inflammatory characteristics. By weaving thin elastomer fibres a graft was generated. The previously described Chandler loop was used to simulate arterial flow conditions ex vivo using rotating PVC tubings filled with human blood. All stents received 120 min of blood contact. To determine thrombocyte activation and inflammatory reaction, the platelet count and levels of beta-TG, TAT and PMN-elastase were assessed. Scanning electron microscopy was used to visualize the reactions. Mechanical polishing and passivation did not improve the stent surface characteristics while sandblasting, electropolishing and aluminium covering decreased activation of the coagulation cascade. In terms of thrombogenicity, the heparin coating had no beneficial effect. The lowest thrombogenic potential was found in the Polyurethane-coated stent group. All stents showed similar levels of polymorph nuclear granulocyte elastase except for the membrane design. While mechanical and chemical modifications are able to reduce thrombogenicity, coating with this particular polyurethane polymer seems to be superior to these approaches regarding the parameters assessed in this experimental setting. The Chandler loop is a valuable tool to test polymeric coatings ex vivo since these modifications may reduce drug performance by inducing inflammatory reaction themselves.