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Milano, Italy

Visalli G.,Messina University | Baluce B.,Cell Factory | Bertuccio M.,Messina University | Picerno I.,Messina University | Di Pietro A.,Messina University
Journal of Toxicology and Environmental Health - Part A: Current Issues

Previously a significant mitochondrial impairment was identified in alveolar epithelial cells exposed to metals adsorbed to combustion-generated particulate matter (PM). Due to the critical role of mitochondria in apoptosis, the aim of this study was to investigate the pro-apoptotic potential of metals present in oil fly ash (OFA). A549 cells were exposed to water-soluble components of an OFA sample, containing vanadium [V(IV)], iron [Fe(III)], and nickel [Ni(II)] (68.8, 110.4, and 18 μM, respectively). Experiments were also performed using individual metal solutions. Apoptosis was detected and the mitochondrial role was assessed by a caspase-9 inhibitor (Z-LEHD-FMK). To determine whether the presence of impaired mitochondria in unexposed daughter cells increased apoptosis, an in vitro model was developed that allowed determination of effects until the third cell generation. To specifically examine the toxicity of vanadium (V), that characterize the airborne pollutant examined in this study, p53involvement and metabolic impairment through changes in HIF-1α and Glut-1 expression were determined. OFA and individual metal solutions produced significant apoptosis in the progeny of exposed cells, triggering the intrinsic apoptosis pathway. In apoptosis induced by poorly genotoxic metal V, p53 did not play a significant role. However, V exposure increased nuclear translocation of HIF-1α and expression of the Glut-1 receptor, indicating metabolic impairment due to metal-induced mitochondrial dysfunction. Overall, these results improve our knowledge of the pathogenic role that airborne metals and in particular V exerted in respiratory epithelium. Copyright © Taylor & Francis Group, LLC. Source

Pierro M.,Cardiovascular Research Center and Pulmonary Research Group | Pierro M.,University of Milan | Ionescu L.,Cardiovascular Research Center and Pulmonary Research Group | Montemurro T.,Cell Factory | And 10 more authors.

Background: Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity and currently lacks efficient treatment. Rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. Human cord is an advantageous source of stem cells that is especially appealing for the treatment of neonatal diseases. The therapeutic benefit after established lung injury and long-term safety of cord-derived stem cells is unknown. Methods: Human cord-derived perivascular cells (PCs) or cord blood-derived MSCs were delivered prophylactically or after established alveolar injury into the airways of newborn rats exposed to hyperoxia, a well-established BPD model. Results: Rat pups exposed to hyperoxia showed the characteristic arrest in alveolar growth with air space enlargement and loss of lung capillaries. PCs and MSCs partially prevented and rescued lung function and structure. Despite therapeutic benefit, cell engraftment was low, suggesting that PCs and MSCs act via a paracrine effect. Accordingly, cell free-derived conditioned media from PCs and MSCs also exerted therapeutic benefit when used either prophylactically or therapeutically. Finally, long-term (6 months) assessment of stem cell or conditioned media therapy showed no adverse lung effects of either strategy, with persistent improvement in exercise capacity and lung structure. Conclusions: Human umbilical cord-derived PCs and MSCs exert short- and long-term therapeutic benefit without adverse lung effects in this experimental model and offer new therapeutic options for lung diseases characterised by alveolar damage. Source

Murray I.R.,University of Edinburgh | Murray I.R.,Queens Medical Research Institute | Murray I.R.,University of California at Los Angeles | West C.C.,University of Edinburgh | And 13 more authors.
Cellular and Molecular Life Sciences

Mesenchymal stem/stromal cells (MSCs) can regenerate tissues by direct differentiation or indirectly by stimulating angiogenesis, limiting inflammation, and recruiting tissue-specific progenitor cells. MSCs emerge and multiply in long-term cultures of total cells from the bone marrow or multiple other organs. Such a derivation in vitro is simple and convenient, hence popular, but has long precluded understanding of the native identity, tissue distribution, frequency, and natural role of MSCs, which have been defined and validated exclusively in terms of surface marker expression and developmental potential in culture into bone, cartilage, and fat. Such simple, widely accepted criteria uniformly typify MSCs, even though some differences in potential exist, depending on tissue sources. Combined immunohistochemistry, flow cytometry, and cell culture have allowed tracking the artifactual cultured mesenchymal stem/stromal cells back to perivascular anatomical regions. Presently, both pericytes enveloping microvessels and adventitial cells surrounding larger arteries and veins have been described as possible MSC forerunners. While such a vascular association would explain why MSCs have been isolated from virtually all tissues tested, the origin of the MSCs grown from umbilical cord blood remains unknown. In fact, most aspects of the biology of perivascular MSCs are still obscure, from the emergence of these cells in the embryo to the molecular control of their activity in adult tissues. Such dark areas have not compromised intents to use these cells in clinical settings though, in which purified perivascular cells already exhibit decisive advantages over conventional MSCs, including purity, thorough characterization and, principally, total independence from in vitro culture. A growing body of experimental data is currently paving the way to the medical usage of autologous sorted perivascular cells for indications in which MSCs have been previously contemplated or actually used, such as bone regeneration and cardiovascular tissue repair. © 2013 Springer. Source

Corselli M.,Stem Cell Research Center | Corselli M.,University of California at Los Angeles | Corselli M.,Erasmus Medical Center | Chen C.-W.,Stem Cell Research Center | And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology

Independent studies by numerous investigators have shown that it is possible to harvest multipotent progenitor cells from diverse dissociated and cultured fetal, perinatal, and principally adult developed tissues. Despite the increasingly recognized medical value of these progenitor cells, the archetype of which remains the mesenchymal stem cell, this indirect extraction method has precluded the understanding of their native identity, tissue distribution, and frequency. Consistent with other researchers, we have hypothesized that blood vessels in virtually all organs harbor ubiquitous stem cells. We have identified, marked, and sorted to homogeneity by flow cytometry endothelial and perivascular cells in a large selection of human fetal, perinatal, and adult organs. Perivascular cells, including pericytes in the smallest blood vessels and adventitial cells around larger ones, natively express mesenchymal stem cell markers and produce in culture a long-lasting progeny of multilineage mesodermal progenitor cells. Herein, we review results from our and other laboratories that suggest a perivascular origin for mesenchymal stem cells and other adult progenitor cells. Recent experiments illustrate the therapeutic potential of human pericytes to regenerate skeletal muscle and promote functional recovery in the diseased heart and kidney. © 2010 American Heart Association, Inc. Source

Castellani M.,Fondazione IRCCS Ca Granda | Colombo A.,Catheterization Laboratory | Giordano R.,Cell Factory | Pusineri E.,Clinical Cardiology Unit | And 8 more authors.
Journal of Nuclear Medicine

Over the last decade, the effects of stem cell therapy on cardiac repair after acute myocardial infarction (AMI) have been investigated with different imaging techniques. We evaluated a new imaging approach using 13N-ammonia and 18F-FDG PET for a combined analysis of cardiac perfusion, metabolism, and function in patients treated with intracoronary injection of endothelial progenitors or with conventional therapy for AMI. Methods: A total of 15 patients were randomly assigned to 3 groups based on different treatments (group A: bone marrow-derived stem cells; group B: peripheral blood-derived stem cells; group C: standard therapy alone). The number of scarred and viable segments, along with the infarct size and the extent of the viable area, were determined on a 9-segment 13N- ammonia/18F-FDG PET polar map. Myocardial blood flow (MBF) was calculated for each segment on the ammonia polar map, whereas a global evaluation of left ventricular function was obtained by estimating left ventricular ejection fraction (LVEF) and end-diastolic volume, both derived from electrocardiography-gated 18F-FDG images. Both intragroup and intergroup comparative analyses of the mean values of each parameter were performed at baseline and 3, 6, and 12 mo after AMI. During follow-up, major cardiac events were also registered. Results: A significant decrease (P < 0.05) in the number of scarred segments and infarct size was observed in group A, along with an increase in MBF (P < 0.05) and a mild improvement in cardiac function. Lack of infarct size shrinkage in group B was associated with a marked impairment of MBF (P = 0.01) and cardiac dysfunction. Ambiguous changes in infarct size, MBF, and LVEF were found in group C. No differences in number of viable segments or in extent of viable area were found among the groups. At clinical follow-up, no major cardiac events occurred in group A patients, whereas 2 patients of group B experienced in-stent occlusion and one patient of group C received a transplant for heart failure. Conclusion: Our data suggest that a single nuclear imaging technique accurately analyzes changes in myocardial perfusion and metabolism occurring after stem cell transplantation. Copyright © 2010 by the Society of Nuclear Medicine, Inc. Source

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