Prostaglandin E Positively Modulates Endothelial Progenitor Cell Homeostasis: An Advanced Treatment Modality for Autologous Cell Therapy

Aims: The mobilization of endothelial progenitor cells (EPC) and their functioning in postnatal neovascularization are tightly regulated. To identify new modulators of EPC homeostasis, we screened biologically active prostaglandin E compounds for their effects on EPC production, trafficking and function. Methods and Results: We found that EPC are a rich source for prostaglandin E 2 (PGE 2), stimulating their number and function in an auto- and paracrine manner. In vivo blockade of PGE 2 production by selective cyclooxygenase-2 inhibition virtually abrogated ischemia-induced EPC mobilization demonstrating its crucial role in EPC homeostasis following tissue ischemia. Conversely, ex vivo treatment of isolated EPC with the clinically approved PGE 1 analogue alprostadil enhanced EPC number and function. These effects were mediated by increased expression of the chemokine receptor CXCR4 and were dependent on nitric oxide synthase activity. Most importantly, ex vivo PGE 1 pretreatment of isolated EPC significantly enhanced their neovascularization capacity in a murine model of hind limb ischemia as assessed by laser Doppler analysis, exercise stress test and immunohistochemistry. Conclusions: The conserved role for PGE in the regulation of EPC homeostasis suggests that ex vivo modulation of the prostaglandin pathway in isolated progenitor cells may represent a novel and safe strategy to facilitate cell-based therapies. Copyright (C) 2009 S. Karger AG, Base

Human endothelial-like differentiated precursor cells maintain their endothelial characteristics when cocultured with mesenchymal stem cell and seeded onto human cancellous bone

Introduction. Cancellous bone is frequently used for filling bone defects in a clinical setting. It provides favourable conditions for regenerative cells such as MSC and early EPC. The combination of MSC and EPC results in superior bone healing in experimental bone healing models. Materials and Methods. We investigated the influence of osteogenic culture conditions on the endothelial properties of early EPC and the osteogenic properties of MSC when cocultured on cancellous bone. Additionally, cell adhesion, metabolic activity, and differentiation were assessed 2, 6, and 10 days after seeding. Results. The number of adhering EPC and MSC decreased over time; however the cells remained metabolically active over the 10-day measurement period. In spite of a decline of lineage specific markers, cells maintained their differentiation to a reduced level. Osteogenic stimulation of EPC caused a decline but not abolishment of endothelial characteristics and did not induce osteogenic gene expression. Osteogenic stimulation of MSC significantly increased their metabolic activity whereas collagen-1α and alkaline phosphatase gene expressions declined. When cocultured with EPC, MSC’s collagen-1α gene expression increased significantly. Conclusion. EPC and MSC can be cocultured in vitro on cancellous bone under osteogenic conditions, and coculturing EPC with MSC stabilizes the latter’s collagen-1α gene expression

SDF1 Gene Variation Is Associated with Circulating SDF1 alpha Level and Endothelial Progenitor Cell Number-The Bruneck Study

BACKGROUND: Stromal cell-derived factor-1 (SDF1) and its receptor CXC chemokine receptor 4 (CXCR4) play a critical role in progenitor cell homing, mobilization and differentiation. It would be interesting to assess the predictive value of SDF-1alpha level for EPC number, and to ascertain whether there is a relationship between SDF1 gene variation, plasma SDF-1alpha level, and the number and function of circulating EPCs. We also tested whether EPC number and function was related to CXCR4 gene variation. METHODOLOGY AND PRINCIPAL FINDINGS: We genotyped a cohort of individuals who participated in the Bruneck Study for single nucleotide polymorphisms (SNPs) in the SDF1 and CXCR4 genes, and measured blood SDF1alpha level as well as EPC number and function. SDF1alpha levels were correlated with age, gender, alcohol consumption, circulating reticulocyte numbers, and concentrations of matrix metalloproteinase-9, C-reactive protein, cystatin C, fibrinogen and homocytein. In blood samples taken in 2005, EPC number was inversely associated with SDF1alpha level (p<0.001). EPC number in 2005 was also inversely associated with SDF1alpha level in 2000 (p = 0.009), suggesting a predictive value of plasma SDF1alpha level for EPC number. There was an association between the SDF1 gene rs2297630 SNP A/A genotype, increased SDF1alpha level (p = 0.002) and lower EPC number (p = 0.006). CONCLUSIONS: Our data indicate that a SDF1 gene variation (rs2297630) has an influence on SDF1alpha level and circulating EPC number, and that plasma SDF1alpha level is a predictor of EPC number

Exciton-optical phonon coupling in II-VI semiconductor nanocrystals.

This perspective reviews the topic of exciton-phonon coupling (EPC) in II-VI semiconductor nanocrystals. First, EPC is defined and its relevance is discussed, both as it influences the properties of the materials relevant to applications and as a probe of electronic structure. Different experimental and theoretical methods for probing EPC are outlined. Results for several different classes of II-VI nanocrystals are summarized. Finally, possible future directions are outlined

Polimorfismi a Singolo Nucleotide e Cellule Progenitrici Endoteliali

Uno dei più interessanti target della ricerca clinica in campo cardiovascolare degli ultimi anni è rappresentato dalle Cellule Progenitrici Endoteliali (EPC). Queste cellule, che derivano dal midollo osseo, sono in grado di differenziarsi in cellule endoteliali mature e hanno il compito di mantenere l’omeostasi vascolare partecipando ai processi di rinnovamento e riparazione della parete endoteliale. E’ stato ipotizzato che l’attivazione delle EPC avvenga ad opera di vari fattori molecolari secreti direttamente dal tessuto danneggiato quali VEGF e SDF-1α. Recenti studi hanno dimostrato che il numero e l’attività migratoria delle EPC circolanti è inversamente correlato ai fattori di rischio per CAD (coronary artery disease) ed in particolar modo all’iperglicemia che colpisce in maniera importante le EPC, riducendone la sopravvivenza e alterandone il funzionamento probabilmente a causa dello stress ossidativo e dello stato infiammatorio cronico. Scopo di questo lavoro di tesi è studiare varianti polimorfiche nei geni implicati nei processi di infiammazione e di attivazione delle EPC, al fine di individuare marcatori che correlino col numero di cellule endoteliali circolanti. Tramite l’analisi al citofluorimetro (FACS) sono state quantificate le EPC in una coorte di soggetti costituita da 18 diabetici di tipo II di nuova diagnosi, 34 pre-diabetici e 26 normoglicemici. Per validare la significatività di alcuni dati è stato possibile ampliare la popolazione studiata con ulteriori 62 soggetti. La tecnica della Real-Time PCR con metodo Taqman ha permesso di genotipizzare 12 SNP in 12 geni ottenendo come risultato associazioni significative tra i livelli delle EPC e i polimorfismi rs2070874 dell’IL-4, rs1800629 del TNF-α e rs5498 di ICAM-1. I livelli di EPC circolanti tra soggetti con genotipo C/C vs T/T per il polimorfismo rs2070875 dell’IL-4 sono risultati significativamente diversi (p-value=0,0388), mentre è al limite della significatività la differenza tra eterozigoti C/T vs T/T (p-value=0,0625). Tuttavia, questo dato potrebbe dipendere dal fatto che il genotipo T/T è presente in un unico soggetto. Il polimorfismo rs1800629 del TNF-α è risultato significativamente associato ai livelli di EPC. Soggetti con genotipo G/G presentano livelli di EPC minori di soggetti con genotipo A/A (p-value=0,0022). A causa della presenza di un solo soggetto con genotipo A/A, abbiamo accorpato i soggetti G/A e A/A per valutare l’associazione del cluster G/A+A/A vs G/G ed EPC circolanti. L’associazione rimane statisticamente significativa (p-value=0,0039). La significatività dei risultati è stata confermata anche a seguito dell’ampliamento della popolazione iniziale con l’aggiunta di 62 soggetti. Anche il polimorfismo rs5498 di ICAM-1 ha mostrato un trend di associazione positivo con i livelli di EPC. In particolare, il genotipo A/A vs G/G presenta un valore significativamente minore di cellule (p-value=0,02924), mentre è ai limiti della significatività la differenza tra G/A e G/G (p-value=0,0678). Anche in questo caso abbiamo raggruppato i soggetti A/A e G/A, per verificare l’associazione del cluster A/A+G/A vs G/G ed EPC circolanti ottenendo un p-value pari a 0,0302. A seguito dell’aggiunta nello studio degli ulteriori 62 soggetti, l’associazione risulta meno evidente e tra i genotipi A/A+G/A rispetto ai G/G perde la significatività statistica

Toxicity of Pb and of Pb/Cd combination on the springtail Folsomia candida in natural soils: Reproduction, growth and bioaccumulation as indicators

The toxicity of Pb and Cd+Pb was assessed on the Collembola F. candida in two cultivated soils (SV and AU) with low organic matter (OM) content and circumneutral to basic pH, and an acid forested soil (EPC) with high OM content. Collembola reproduction and growth as well as metal content in Collembola body, in soil, exchangeable fraction and soil solutions, pH and DOC were investigated. Pb and Cd+Pb were the highest in exchangeable fraction and soil solution of the acidic soils. Soil solution pH decreased after metal spiking in every soil due to metal adsorption, which was similar for Cd and the highest in AU for Pb. With increasing Pb and Cd+Pb, the most important reproduction decrease was in EPC soil. The LOEC for reproduction after metal addition was 2400 (Pb) and 200/2400 (Cd/Pb), 1200 and 100/1200, 300 and 100/1200 μg g−1 for AU, SV and EPC, respectively. The highest and the lowest Pb toxicity was observed for EPC and AU bulk soil, respectively. The metal in Collembola increased with increasing soil concentration, except in AU, but the decreasing BFsolution with increasing concentrations indicates a limited metal transfer to Collembola or an increased metal removal. Loading high Pb concentrations decreases Cd absorption by the Collembola, but the reverse was not true. The highest Pb toxicity in EPC can be explained by pH and OM content. Because of metal complexation, OM might have a protective role but its ingestion by Collembola lead to higher toxicity. Metal bioavailability in Collembola differs from soil solution indicating that soil solution is not sufficient to evaluate toxicity in soil organisms. The toxicity as a whole decreased when metals were combined, except for Pb in AU, due to adsorption competition between Cd and Pb on clay particles and OM sites in AU and EPC soils, respectively

Enabling Disaster Resilient 4G Mobile Communication Networks

The 4G Long Term Evolution (LTE) is the cellular technology expected to outperform the previous generations and to some extent revolutionize the experience of the users by taking advantage of the most advanced radio access techniques (i.e. OFDMA, SC-FDMA, MIMO). However, the strong dependencies between user equipments (UEs), base stations (eNBs) and the Evolved Packet Core (EPC) limit the flexibility, manageability and resiliency in such networks. In case the communication links between UEs-eNB or eNB-EPC are disrupted, UEs are in fact unable to communicate. In this article, we reshape the 4G mobile network to move towards more virtual and distributed architectures for improving disaster resilience, drastically reducing the dependency between UEs, eNBs and EPC. The contribution of this work is twofold. We firstly present the Flexible Management Entity (FME), a distributed entity which leverages on virtualized EPC functionalities in 4G cellular systems. Second, we introduce a simple and novel device-todevice (D2D) communication scheme allowing the UEs in physical proximity to communicate directly without resorting to the coordination with an eNB.Comment: Submitted to IEEE Communications Magazin