Publications by authors named "Maurizio Muraca"

76 Publications

Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia.

Am J Physiol Lung Cell Mol Physiol 2021 Jan 27. Epub 2021 Jan 27.

Department of Women's and Children's Health, University of Padova.

Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: a) animals raised in ambient air for 6 weeks (n=10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with b) IT-administered saline solution (n=10), or c) MSC-EVs (n=10) on postnatal days 3, 7, 10 and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings furtherly support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodelling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.
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http://dx.doi.org/10.1152/ajplung.00148.2020DOI Listing
January 2021

Muscle functional recovery is driven by extracellular vesicles combined with muscle extracellular matrix in a volumetric muscle loss murine model.

Biomaterials 2021 Feb 7;269:120653. Epub 2021 Jan 7.

Stem Cells and Regenerative Medicine Lab, Institute of Pediatric Research Città Della Speranza, Padova, Italy; Department of Women and Children Health, University of Padova, Italy. Electronic address:

Biological scaffolds derived from decellularized tissues are being investigated as a promising approach to repair volumetric muscle losses (VML). Indeed, extracellular matrix (ECM) from decellularized tissues is highly biocompatible and mimics the original tissue. However, the development of fibrosis and the muscle stiffness still represents a major problem. Intercellular signals mediating tissue repair are conveyed via extracellular vesicles (EVs), biologically active nanoparticles secreted by the cells. This work aimed at using muscle ECM and human EVs derived from Wharton Jelly mesenchymal stromal cells (MSC EVs) to boost tissue regeneration in a VML murine model. Mice transplanted with muscle ECM and treated with PBS or MSC EVs were analyzed after 7 and 30 days. Flow cytometry, tissue analysis, qRT-PCR and physiology test were performed. We demonstrated that angiogenesis and myogenesis were enhanced while fibrosis was reduced after EV treatment. Moreover, the inflammation was directed toward tissue repair. M2-like, pro-regenerative macrophages were significantly increased in the MSC EVs treated group compared to control. Strikingly, the histological improvements were associated with enhanced functional recovery. These results suggest that human MSC EVs can be a naturally-derived boost able to ameliorate the efficacy of tissue-specific ECM in muscle regeneration up to the restored tissue function.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120653DOI Listing
February 2021

Administration of Human MSC-Derived Extracellular Vesicles for the Treatment of Primary Sclerosing Cholangitis: Preclinical Data in MDR2 Knockout Mice.

Int J Mol Sci 2020 Nov 23;21(22). Epub 2020 Nov 23.

Department of Biomedical Sciences, University of Padova and Fondazione Istituto di Ricerca Pediatrica-Città della Speranza, 35127 Padova, Italy.

Primary Sclerosing Cholangitis (PSC) is a progressive liver disease for which there is no effective medical therapy. PSC belongs to the family of immune-mediated biliary disorders and it is characterized by persistent biliary inflammation and fibrosis. Here, we explored the possibility of using extracellular vesicles (EVs) derived from human, bone marrow mesenchymal stromal cells (MSCs) to target liver inflammation and reduce fibrosis in a mouse model of PSC. Five-week-old male FVB.129P2-Abcb mice were intraperitoneally injected with either 100 µL of EVs (± 9.1 × 10 particles/mL) or PBS, once a week, for three consecutive weeks. One week after the last injection, mice were sacrificed and liver and blood collected for flow cytometry analysis and transaminase quantification. In FVB.129P2-Abcb4 mice, EV administration resulted in reduced serum levels of alkaline phosphatase (ALP), bile acid (BA), and alanine aminotransferase (ALT), as well as in decreased liver fibrosis. Mechanistically, we observed that EVs reduce liver accumulation of both granulocytes and T cells and dampen VCAM-1 expression. Further analysis revealed that the therapeutic effect of EVs is accompanied by the inhibition of NFkB activation in proximity of the portal triad. Our pre-clinical experiments suggest that EVs isolated from MSCs may represent an effective therapeutic strategy to treat patients suffering from PSC.
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http://dx.doi.org/10.3390/ijms21228874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700340PMC
November 2020

The Role of Extracellular Vesicles (EVs) in the Epigenetic Regulation of Bone Metabolism and Osteoporosis.

Int J Mol Sci 2020 Nov 17;21(22). Epub 2020 Nov 17.

Research Laboratories, Department of Onco-hematology, Pediatric Hospital Bambino Gesù, 00146 Rome, Italy.

Extracellular vesicles (EVs) are complex phospholipidic structures actively released by cells. EVs are recognized as powerful means of intercellular communication since they contain many signaling molecules (including lipids, proteins, and nucleic acids). In parallel, changes in epigenetic processes can lead to changes in gene function and finally lead to disease onset and progression. Recent breakthroughs have revealed the complex roles of non-coding RNAs (microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)) in epigenetic regulation. Moreover, a substantial body of evidence demonstrates that non-coding RNAs can be shuttled among the cells and tissues via EVs, allowing non-coding RNAs to reach distant cells and exert systemic effects. Resident bone cells, including osteoclasts, osteoblasts, osteocytes, and endothelial cells, are tightly regulated by non-coding RNAs, and many of them can be exported from the cells to neighboring ones through EVs, triggering pathological conditions. For these reasons, researchers have also started to exploit EVs as a theranostic tool to address osteoporosis. In this review, we summarize some recent findings regarding the EVs' involvement in the fine regulation of non-coding RNAs in the context of bone metabolism and osteoporosis.
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http://dx.doi.org/10.3390/ijms21228682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698531PMC
November 2020

Mesenchymal stromal cells and their secreted extracellular vesicles as therapeutic tools for COVID-19 pneumonia?

J Control Release 2020 09 3;325:135-140. Epub 2020 Jul 3.

Department of Women's and Children's Health, University of Padova, Italy.

The COVID-19 epidemic represents an unprecedented global health emergency, further aggravated by the lack of effective therapies. For this reason, several clinical trials are testing different off-label drugs, already approved for other pathologies. Mesenchymal stem/stromal cells (MSCs) have been tested during the last two decades for the treatment of various pathologic conditions, including acute and chronic lung diseases, both in animal models and in patients. In particular, promising results have been obtained in the experimental therapy of acute respiratory distress syndrome, which represents the most threatening complication of COVID-19 infection. Furthermore, more recently, great interest has been devoted to the possible clinical applications of extracellular vesicles secreted by MSCs, nanoparticles that convey much of the biological effects and of the therapeutic efficacy of their cells of origin. This review summarizes the experimental evidence underlying the possible use of MSCs and of MSC-EVs in severe COVID-19 infection and underlines the need to evaluate the possible efficacy of these therapeutic approaches through controlled studies under the supervision of the Regulatory Authorities.
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http://dx.doi.org/10.1016/j.jconrel.2020.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332437PMC
September 2020

CD73 extracellular vesicles inhibit angiogenesis through adenosine A receptor signalling.

J Extracell Vesicles 2020 4;9(1):1757900. Epub 2020 May 4.

Department of Biomedical Sciences, University of Padua, Padua, Italy.

Pathological angiogenesis is a hallmark of several conditions including eye diseases, inflammatory diseases, and cancer. Stromal cells play a crucial role in regulating angiogenesis through the release of soluble factors or direct contact with endothelial cells. Here, we analysed the properties of the extracellular vesicles (EVs) released by bone marrow mesenchymal stromal cells (MSCs) and explored the possibility of using them to therapeutically target angiogenesis. We demonstrated that in response to pro-inflammatory cytokines, MSCs produce EVs that are enriched in TIMP-1, CD39 and CD73 and inhibit angiogenesis targeting both extracellular matrix remodelling and endothelial cell migration. We identified a novel anti-angiogenic mechanism based on adenosine production, triggering of A adenosine receptors, and induction of NOX2-dependent oxidative stress within endothelial cells. Finally, in pilot experiments, we exploited the anti-angiogenic EVs to inhibit tumour progression . Our results identify novel pathways involved in the crosstalk between endothelial and stromal cell and suggest new therapeutic strategies to target pathological angiogenesis.
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http://dx.doi.org/10.1080/20013078.2020.1757900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241475PMC
May 2020

Present and Future of Bronchopulmonary Dysplasia.

J Clin Med 2020 May 20;9(5). Epub 2020 May 20.

Neonatal Intensive Care Unit, Department of Women's and Children's Health, University of Padova, 35128 Padova, Italy.

Bronchopulmonary dysplasia (BPD) is the most common respiratory disorder among infants born extremely preterm. The pathogenesis of BPD involves multiple prenatal and postnatal mechanisms affecting the development of a very immature lung. Their combined effects alter the lung's morphogenesis, disrupt capillary gas exchange in the alveoli, and lead to the pathological and clinical features of BPD. The disorder is ultimately the result of an aberrant repair response to antenatal and postnatal injuries to the developing lungs. Neonatology has made huge advances in dealing with conditions related to prematurity, but efforts to prevent and treat BPD have so far been only partially effective. Seeing that BPD appears to have a role in the early origin of chronic obstructive pulmonary disease, its prevention is pivotal also in long-term respiratory outcome of these patients. There is currently some evidence to support the use of antenatal glucocorticoids, surfactant therapy, protective noninvasive ventilation, targeted saturations, early caffeine treatment, vitamin A, and fluid restriction, but none of the existing strategies have had any significant impact in reducing the burden of BPD. New areas of research are raising novel therapeutic prospects, however. For instance, early topical (intratracheal or nebulized) steroids seem promising: they might help to limit BPD development without the side effects of systemic steroids. Evidence in favor of stem cell therapy has emerged from several preclinical trials, and from a couple of studies in humans. Mesenchymal stromal/stem cells (MSCs) have revealed a reparatory capability, preventing the progression of BPD in animal models. Administering MSC-conditioned media containing extracellular vesicles (EVs) have also demonstrated a preventive action, without the potential risks associated with unwanted engraftment or the adverse effects of administering cells. In this paper, we explore these emerging treatments and take a look at the revolutionary changes in BPD and neonatology on the horizon.
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http://dx.doi.org/10.3390/jcm9051539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290764PMC
May 2020

International Society for Extracellular Vesicles and International Society for Cell and Gene Therapy statement on extracellular vesicles from mesenchymal stromal cells and other cells: considerations for potential therapeutic agents to suppress coronavirus disease-19.

Cytotherapy 2020 09 16;22(9):482-485. Epub 2020 May 16.

Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address:

Statement: The International Society for Cellular and Gene Therapies (ISCT) and the International Society for Extracellular Vesicles (ISEV) recognize the potential of extracellular vesicles (EVs, including exosomes) from mesenchymal stromal cells (MSCs) and possibly other cell sources as treatments for COVID-19. Research and trials in this area are encouraged. However, ISEV and ISCT do not currently endorse the use of EVs or exosomes for any purpose in COVID-19, including but not limited to reducing cytokine storm, exerting regenerative effects or delivering drugs, pending the generation of appropriate manufacturing and quality control provisions, pre-clinical safety and efficacy data, rational clinical trial design and proper regulatory oversight.
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http://dx.doi.org/10.1016/j.jcyt.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229942PMC
September 2020

Human bone marrow mesenchymal stem cell-derived extracellular vesicles attenuate neuroinflammation evoked by focal brain injury in rats.

J Neuroinflammation 2019 Nov 13;16(1):216. Epub 2019 Nov 13.

NeuroRepair Department, Mossakowski Medical Research Centre, PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland.

Background: Ischemic stroke is the major cause of long-term severe disability and death in aged population. Cell death in the infarcted region of the brain induces immune reaction leading to further progression of tissue damage. Immunomodulatory function of mesenchymal stem cells (MSCs) has been shown in multiple preclinical studies; however, it has not been successfully translated to a routine clinical practice due to logistical, economical, regulatory, and intellectual property obstacles. It has been recently demonstrated that therapeutic effect of intravenously administered MSCs can be recapitulated by extracellular vesicles (EVs) derived from them. However, in contrast to MSCs, EVs were not capable to decrease stroke-induced neuroinflammation. Therefore, the aim of the study was to investigate if intra-arterial delivery of MSC-derived EVs will have stronger impact on focal brain injury-induced neuroinflammation, which mimics ischemic stroke, and how it compares to MSCs.

Methods: The studies were performed in adult male Wistar rats with focal brain injury induced by injection of 1 μl of 50 nmol ouabain into the right hemisphere. Two days after brain insult, 5 × 10 human bone marrow MSCs (hBM-MSCs) labeled with Molday ION or 1.3 × 10 EVs stained with PKH26 were intra-arterially injected into the right hemisphere under real-time MRI guidance. At days 1, 3, and 7 post-transplantation, the rats were decapitated, the brains were removed, and the presence of donor cells or EVs was analyzed. The cellular immune response in host brain was evaluated immunohistochemically, and humoral factors were measured by multiplex immunoassay.

Results: hBM-MSCs and EVs transplanted intra-arterially were observed in the rat ipsilateral hemisphere, near the ischemic region. Immunohistochemical analysis of brain tissue showed that injection of hBM-MSCs or EVs leads to the decrease of cell activation by ischemic injury, i.e., astrocytes, microglia, and infiltrating leucocytes, including T cytotoxic cells. Furthermore, we observed significant decrease of pro-inflammatory cytokines and chemokines after hBM-MSC or EV infusion comparing with non-treated rats with focal brain injury.

Conclusions: Intra-arterially injected EVs attenuated neuroinflammation evoked by focal brain injury, which mimics ischemic stroke, and this effect was comparable to intra-arterial hBM-MSC transplantation. Thus, intra-arterial injection of EVs might be an attractive therapeutic approach, which obviates MSC-related obstacles.
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http://dx.doi.org/10.1186/s12974-019-1602-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852925PMC
November 2019

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells.

J Bone Miner Res 2020 02 5;35(2):396-412. Epub 2019 Nov 5.

Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.

Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell-derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3891DOI Listing
February 2020

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.

Authors:
Clotilde Théry Kenneth W Witwer Elena Aikawa Maria Jose Alcaraz Johnathon D Anderson Ramaroson Andriantsitohaina Anna Antoniou Tanina Arab Fabienne Archer Georgia K Atkin-Smith D Craig Ayre Jean-Marie Bach Daniel Bachurski Hossein Baharvand Leonora Balaj Shawn Baldacchino Natalie N Bauer Amy A Baxter Mary Bebawy Carla Beckham Apolonija Bedina Zavec Abderrahim Benmoussa Anna C Berardi Paolo Bergese Ewa Bielska Cherie Blenkiron Sylwia Bobis-Wozowicz Eric Boilard Wilfrid Boireau Antonella Bongiovanni Francesc E Borràs Steffi Bosch Chantal M Boulanger Xandra Breakefield Andrew M Breglio Meadhbh Á Brennan David R Brigstock Alain Brisson Marike Ld Broekman Jacqueline F Bromberg Paulina Bryl-Górecka Shilpa Buch Amy H Buck Dylan Burger Sara Busatto Dominik Buschmann Benedetta Bussolati Edit I Buzás James Bryan Byrd Giovanni Camussi David Rf Carter Sarah Caruso Lawrence W Chamley Yu-Ting Chang Chihchen Chen Shuai Chen Lesley Cheng Andrew R Chin Aled Clayton Stefano P Clerici Alex Cocks Emanuele Cocucci Robert J Coffey Anabela Cordeiro-da-Silva Yvonne Couch Frank Aw Coumans Beth Coyle Rossella Crescitelli Miria Ferreira Criado Crislyn D'Souza-Schorey Saumya Das Amrita Datta Chaudhuri Paola de Candia Eliezer F De Santana Olivier De Wever Hernando A Del Portillo Tanguy Demaret Sarah Deville Andrew Devitt Bert Dhondt Dolores Di Vizio Lothar C Dieterich Vincenza Dolo Ana Paula Dominguez Rubio Massimo Dominici Mauricio R Dourado Tom Ap Driedonks Filipe V Duarte Heather M Duncan Ramon M Eichenberger Karin Ekström Samir El Andaloussi Celine Elie-Caille Uta Erdbrügger Juan M Falcón-Pérez Farah Fatima Jason E Fish Miguel Flores-Bellver András Försönits Annie Frelet-Barrand Fabia Fricke Gregor Fuhrmann Susanne Gabrielsson Ana Gámez-Valero Chris Gardiner Kathrin Gärtner Raphael Gaudin Yong Song Gho Bernd Giebel Caroline Gilbert Mario Gimona Ilaria Giusti Deborah Ci Goberdhan André Görgens Sharon M Gorski David W Greening Julia Christina Gross Alice Gualerzi Gopal N Gupta Dakota Gustafson Aase Handberg Reka A Haraszti Paul Harrison Hargita Hegyesi An Hendrix Andrew F Hill Fred H Hochberg Karl F Hoffmann Beth Holder Harry Holthofer Baharak Hosseinkhani Guoku Hu Yiyao Huang Veronica Huber Stuart Hunt Ahmed Gamal-Eldin Ibrahim Tsuneya Ikezu Jameel M Inal Mustafa Isin Alena Ivanova Hannah K Jackson Soren Jacobsen Steven M Jay Muthuvel Jayachandran Guido Jenster Lanzhou Jiang Suzanne M Johnson Jennifer C Jones Ambrose Jong Tijana Jovanovic-Talisman Stephanie Jung Raghu Kalluri Shin-Ichi Kano Sukhbir Kaur Yumi Kawamura Evan T Keller Delaram Khamari Elena Khomyakova Anastasia Khvorova Peter Kierulf Kwang Pyo Kim Thomas Kislinger Mikael Klingeborn David J Klinke Miroslaw Kornek Maja M Kosanović Árpád Ferenc Kovács Eva-Maria Krämer-Albers Susanne Krasemann Mirja Krause Igor V Kurochkin Gina D Kusuma Sören Kuypers Saara Laitinen Scott M Langevin Lucia R Languino Joanne Lannigan Cecilia Lässer Louise C Laurent Gregory Lavieu Elisa Lázaro-Ibáñez Soazig Le Lay Myung-Shin Lee Yi Xin Fiona Lee Debora S Lemos Metka Lenassi Aleksandra Leszczynska Isaac Ts Li Ke Liao Sten F Libregts Erzsebet Ligeti Rebecca Lim Sai Kiang Lim Aija Linē Karen Linnemannstöns Alicia Llorente Catherine A Lombard Magdalena J Lorenowicz Ákos M Lörincz Jan Lötvall Jason Lovett Michelle C Lowry Xavier Loyer Quan Lu Barbara Lukomska Taral R Lunavat Sybren Ln Maas Harmeet Malhi Antonio Marcilla Jacopo Mariani Javier Mariscal Elena S Martens-Uzunova Lorena Martin-Jaular M Carmen Martinez Vilma Regina Martins Mathilde Mathieu Suresh Mathivanan Marco Maugeri Lynda K McGinnis Mark J McVey David G Meckes Katie L Meehan Inge Mertens Valentina R Minciacchi Andreas Möller Malene Møller Jørgensen Aizea Morales-Kastresana Jess Morhayim François Mullier Maurizio Muraca Luca Musante Veronika Mussack Dillon C Muth Kathryn H Myburgh Tanbir Najrana Muhammad Nawaz Irina Nazarenko Peter Nejsum Christian Neri Tommaso Neri Rienk Nieuwland Leonardo Nimrichter John P Nolan Esther Nm Nolte-'t Hoen Nicole Noren Hooten Lorraine O'Driscoll Tina O'Grady Ana O'Loghlen Takahiro Ochiya Martin Olivier Alberto Ortiz Luis A Ortiz Xabier Osteikoetxea Ole Østergaard Matias Ostrowski Jaesung Park D Michiel Pegtel Hector Peinado Francesca Perut Michael W Pfaffl Donald G Phinney Bartijn Ch Pieters Ryan C Pink David S Pisetsky Elke Pogge von Strandmann Iva Polakovicova Ivan Kh Poon Bonita H Powell Ilaria Prada Lynn Pulliam Peter Quesenberry Annalisa Radeghieri Robert L Raffai Stefania Raimondo Janusz Rak Marcel I Ramirez Graça Raposo Morsi S Rayyan Neta Regev-Rudzki Franz L Ricklefs Paul D Robbins David D Roberts Silvia C Rodrigues Eva Rohde Sophie Rome Kasper Ma Rouschop Aurelia Rughetti Ashley E Russell Paula Saá Susmita Sahoo Edison Salas-Huenuleo Catherine Sánchez Julie A Saugstad Meike J Saul Raymond M Schiffelers Raphael Schneider Tine Hiorth Schøyen Aaron Scott Eriomina Shahaj Shivani Sharma Olga Shatnyeva Faezeh Shekari Ganesh Vilas Shelke Ashok K Shetty Kiyotaka Shiba Pia R-M Siljander Andreia M Silva Agata Skowronek Orman L Snyder Rodrigo Pedro Soares Barbara W Sódar Carolina Soekmadji Javier Sotillo Philip D Stahl Willem Stoorvogel Shannon L Stott Erwin F Strasser Simon Swift Hidetoshi Tahara Muneesh Tewari Kate Timms Swasti Tiwari Rochelle Tixeira Mercedes Tkach Wei Seong Toh Richard Tomasini Ana Claudia Torrecilhas Juan Pablo Tosar Vasilis Toxavidis Lorena Urbanelli Pieter Vader Bas Wm van Balkom Susanne G van der Grein Jan Van Deun Martijn Jc van Herwijnen Kendall Van Keuren-Jensen Guillaume van Niel Martin E van Royen Andre J van Wijnen M Helena Vasconcelos Ivan J Vechetti Tiago D Veit Laura J Vella Émilie Velot Frederik J Verweij Beate Vestad Jose L Viñas Tamás Visnovitz Krisztina V Vukman Jessica Wahlgren Dionysios C Watson Marca Hm Wauben Alissa Weaver Jason P Webber Viktoria Weber Ann M Wehman Daniel J Weiss Joshua A Welsh Sebastian Wendt Asa M Wheelock Zoltán Wiener Leonie Witte Joy Wolfram Angeliki Xagorari Patricia Xander Jing Xu Xiaomei Yan María Yáñez-Mó Hang Yin Yuana Yuana Valentina Zappulli Jana Zarubova Vytautas Žėkas Jian-Ye Zhang Zezhou Zhao Lei Zheng Alexander R Zheutlin Antje M Zickler Pascale Zimmermann Angela M Zivkovic Davide Zocco Ewa K Zuba-Surma

J Extracell Vesicles 2018 23;7(1):1535750. Epub 2018 Nov 23.

Jagiellonian University, Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Kraków, Poland.

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
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http://dx.doi.org/10.1080/20013078.2018.1535750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322352PMC
November 2018

Intratracheal administration of clinical-grade mesenchymal stem cell-derived extracellular vesicles reduces lung injury in a rat model of bronchopulmonary dysplasia.

Am J Physiol Lung Cell Mol Physiol 2019 01 4;316(1):L6-L19. Epub 2018 Oct 4.

Institute of Pediatric Research, "Città della Speranza," Padua, Italy.

Mesenchymal stem cells (MSCs) prevent the onset of bronchopulmonary dysplasia (BPD) in animal models, an effect that seems to be mediated by their secreted extracellular vesicles (EVs). The aim of this study was to compare the protective effects of intratracheally (IT) administered MSCs versus MSC-EVs in a hyperoxia-induced rat model of BPD. At birth, rats were distributed as follows: animals raised in ambient air for 2 wk ( n = 10), and animals exposed to 60% oxygen for 2 wk and treated with IT-administered physiological solution ( n = 10), MSCs ( n = 10), or MSC-EVs ( n = 10) on postnatal days 3, 7, and 10. The sham-treated hyperoxia-exposed animals showed reductions in total surface area of alveolar air spaces, and total number of alveoli ( N), and an increased mean alveolar volume (V). EVs prompted a significant increase in N ( P < 0.01) and a significant decrease in V ( P < 0.05) compared with sham-treated animals, whereas MSCs only significantly improved N ( P < 0.05). Small pulmonary vessels of the sham-treated hyperoxia-exposed rats also showed an increase in medial thickness, which only EVs succeeded in preventing significantly ( P < 0.05). In conclusion, both EVs and MSCs reduce hyperoxia-induced damage, with EVs obtaining better results in terms of alveolarization and lung vascularization parameters. This suggests that IT-administered EVs could be an effective approach to BPD treatment.
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http://dx.doi.org/10.1152/ajplung.00109.2018DOI Listing
January 2019

Bronchopulmonary dysplasia: what's new on the horizon?

Lancet Child Adolesc Health 2018 08 27;2(8):549-551. Epub 2018 Jun 27.

Department of Women's and Children's Health, Neonatal Intensive Care Unit, Stem Cell and Regenerative Medicine Laboratory, Institute of Pediatric Research Città della Speranza, University of Padova, Padova 35128, Italy. Electronic address:

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http://dx.doi.org/10.1016/S2352-4642(18)30181-0DOI Listing
August 2018

Phenotypic typing and epidemiological survey of antifungal resistance of species detected in clinical samples of Italian patients in a 17 months' period.

Germs 2018 Jun 4;8(2):58-66. Epub 2018 Jun 4.

PhD, Unit of Parasitology, Children's Hospital and Research Institute Bambino Gesú, Piazza Sant'Onofrio 4, Rome, 00165, Italy.

Introduction: Yeast pathogens are emerging agents of nosocomial as well as community-acquired infections and their rapid and accurate identification is crucial for a better management of high-risk patients and for an adequate treatment.

Methods: We performed a retrospective review of 156 yeast isolates collected during a 17 months' period of regular clinical practice at the Microbiology Department of San Camillo Hospital in Treviso, Italy and analyzed by the traditional culture-based method combined with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS).

Results: Out of all the samples collected MALDI-TOF MS was able to characterize with a MT score ≥1.7 (accurate result at species level) 12 different yeast and yeast-like species from 140 samples: (63.7%), (13.6%), (6.5%), (5.7%), (2.1%), (2.1%), (2.1%), (1.4%), (0.7%), (0.7%), (0.7%), (0.7%). Susceptibility testing toward seven common antifungal agents showed a characteristic MIC distribution of isolates for echinocandins: particularly we noticed that 72% and 46% of showed an MIC value close to clinical breakpoint as defined by EUCAST, respectively for anidulafungin and micafungin.

Conclusion: Accurate identification of microorganisms and the study of their antifungal susceptibility allow to understand the epidemiology of a particular area, permitting the choice of the most appropriate early antifungal treatment.
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http://dx.doi.org/10.18683/germs.2018.1132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019954PMC
June 2018

Imaging of extracellular vesicles derived from human bone marrow mesenchymal stem cells using fluorescent and magnetic labels.

Int J Nanomedicine 2018 19;13:1653-1664. Epub 2018 Mar 19.

NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Background: Mesenchymal stem cells have been shown therapeutic in various neurological disorders. Recent studies support the notion that the predominant mechanism by which MSCs act is through the release of extracellular vesicles (EVs). EVs seem to have similar therapeutic activity as their cellular counterparts and may represent an interesting alternative standalone therapy for various diseases. The aim of the study was to optimize the method of EV imaging to better understand therapeutic effects mediated by EVs.

Methods: The fluorescent lipophilic stain PKH26 and superparamagnetic iron oxide nanoparticles conjugated with rhodamine (Molday ION Rhodamine B™) were used for the labeling of vesicles in human bone marrow MSCs (hBM-MSCs). The entire cycle from intracellular vesicles to EVs followed by their uptake by hBM-MSCs has been studied. The identity of vesicles has been proven by antibodies against: anti-CD9, -CD63, and -CD81 (tetraspanins). NanoSight particle tracking analysis (NTA), high-resolution flow cytometric analysis, transmission electron microscopy (TEM), ELYRA PS.1 super-resolution microscopy, and magnetic resonance imaging (MRI) were used for the characterization of vesicles.

Results: The PKH26 and Molday ION were exclusively localized in intracellular vesicles positively stained for EV markers: CD9, CD63, and CD81. The isolated EVs represent heterogeneous population of various sizes as confirmed by NTA. The TEM and MRI were capable to show successful labeling of EVs using ION. Co-culture of EVs with hBM-MSCs revealed their uptake by cells in vitro, as visualized by the co-localization of PKH26 or Molday ION with tetraspanins inside hBM-MSCs.

Conclusion: PKH26 and Molday ION seem to be biocompatible with EVs, and the labeling did not interfere with the capability of EVs to re-enter hBM-MSCs during co-culture in vitro. Magnetic properties of IONs provide an additional advantage for the imaging of EV using TEM and MRI.
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http://dx.doi.org/10.2147/IJN.S159404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865569PMC
May 2018

Exosome Treatment of Bronchopulmonary Dysplasia: How Pure Should Your Exosome Preparation Be?

Am J Respir Crit Care Med 2018 04;197(7):969-970

1 University of Padova Padova, Italy.

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http://dx.doi.org/10.1164/rccm.201709-1851LEDOI Listing
April 2018

Calibrated automated thrombogram values in infants with cardiac surgery before and after cardiopulmonary bypass.

Thromb Res 2017 Dec 21;160:91-96. Epub 2017 Sep 21.

Department of Medicine, Division of Pediatrics, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy.

Introduction: Impaired thrombin generation has been associated to increase bleeding after cardiac surgery with cardiopulmonary bypass (CPB), especially in children. The aim of this study was to evaluate standard coagulation assay, thrombin generation by calibrated automated thrombogram (CAT), thromboelastography (TEG) and procoagulant phospholipids (PPL) activity in infants undergoing cardiac surgery with CPB.

Materials And Methods: Prospective observational study performed in children aged <24months undergoing cardiac surgery with CPB. Exclusion criteria were preoperative coagulopathy or anticoagulant therapy. Coagulation was evaluated by standard coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen level, platelet count), TEG, CAT and PPL at anaesthesia induction (T1) and after 12h (T2). Perioperative bleeding management was performed according to the institutional guidelines.

Results: Forty-nine children aged <24months were enrolled. At T1 ETP and peak height evaluated by CAT were significantly lower in infants aged <6months. Standard coagulation tests, TEG and PPL did not correlate with age. At T2 platelet count, plasmatic fibrinogen level, all TEG parameters, ETP and peak height by CAT were significantly impaired compared to baseline values (T1), despite allogeneic blood product transfusions.

Conclusions: Thrombin generation is significantly impaired in children affected by congenital heart disease, compared to healthy children and adults. CAT parameters resulted age-dependent, and thrombin generation is lower in infants aged <6months. After cardiac surgery with CPB, a coaugulopathy, revealed by CAT, TEG, but not by PT and aPTT assays, is persistent 12h after surgery despite transfusions of blood products.
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http://dx.doi.org/10.1016/j.thromres.2017.09.021DOI Listing
December 2017

Osteoblast-Derived Extracellular Vesicles Are Biological Tools for the Delivery of Active Molecules to Bone.

J Bone Miner Res 2018 03 11;33(3):517-533. Epub 2017 Dec 11.

Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.

Extracellular vesicles (EVs) are newly appreciated regulators of tissue homeostasis and a means of intercellular communication. Reports have investigated the role of EVs and their cargoes in cellular regulation and have tried to fine-tune their biotechnological use, but to date very little is known on their function in bone biology. To investigate the relevance of EV-mediated communication between bone cells, we isolated EVs from primary mouse osteoblasts and assessed membrane integrity, size, and structure by transmission electron microscopy (TEM) and fluorescence-activated cell sorting (FACS). EVs actively shuttled loaded fluorochromes to osteoblasts, monocytes, and endothelial cells. Moreover, osteoblast EVs contained mRNAs shared with donor cells. Osteoblasts are known to regulate osteoclastogenesis, osteoclast survival, and osteoclast function by the pro-osteoclastic cytokine, receptor activator of nuclear factor κ-B ligand (Rankl). Osteoblast EVs were enriched in Rankl, which increased after PTH treatment. These EVs were biologically active, supporting osteoclast survival. EVs isolated from rankl osteoblasts lost this pro-osteoclastic function, indicating its Rankl-dependence. They integrated ex vivo into murine calvariae, and EV-shuttled fluorochromes were quickly taken up by the bone upon in vivo EV systemic administration. Rankl mice lack the osteoclast lineage and are negative for its specific marker tartrate-resistant acid phosphatase (TRAcP). Treatment of rankl mice with wild-type osteoblast EVs induced the appearance of TRAcP-positive cells in an EV density-dependent manner. Finally, osteoblast EVs internalized and shuttled anti-osteoclast drugs (zoledronate and dasatinib), inhibiting osteoclast activity in vitro and in vivo. We conclude that osteoblast EVs are involved in intercellular communication between bone cells, contribute to the Rankl pro-osteoclastic effect, and shuttle anti-osteoclast drugs, representing a potential means of targeted therapeutic delivery. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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http://dx.doi.org/10.1002/jbmr.3332DOI Listing
March 2018

Challenges and Strategies for Improving the Regenerative Effects of Mesenchymal Stromal Cell-Based Therapies.

Int J Mol Sci 2017 Oct 2;18(10). Epub 2017 Oct 2.

Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, via E. Chianesi 53, Rome 00144, Italy.

Cell-based therapies have the potential to revolutionize current treatments for diseases with high prevalence and related economic and social burden. Unfortunately, clinical trials have made only modest improvements in restoring normal function to degenerating tissues. This limitation is due, at least in part, to the death of transplanted cells within a few hours after transplant due to a combination of mechanical, cellular, and host factors. In particular, mechanical stress during implantation, extracellular matrix loss upon delivery, nutrient and oxygen deprivation at the recipient site, and host inflammatory response are detrimental factors limiting long-term transplanted cell survival. The beneficial effect of cell therapy for regenerative medicine ultimately depends on the number of administered cells reaching the target tissue, their viability, and their promotion of tissue regeneration. Therefore, strategies aiming at improving viable cell engraftment are crucial for regenerative medicine. Here we review the major factors that hamper successful cell engraftment and the strategies that have been studied to enhance the beneficial effects of cell therapy. Moreover, we provide a perspective on whether mesenchymal stromal cell-derived extracellular vesicle delivery, as a cell-free regenerative approach, may circumvent current cell therapy limitations.
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http://dx.doi.org/10.3390/ijms18102087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666769PMC
October 2017

Alveolar Rhabdomyosarcoma Decellularization.

Methods Mol Biol 2018 ;1577:317-325

Department of Women's and Children's Health, University of Padova, Padova, Italy.

In cancer research, it is an urgent need in the obtainment of a simple and reproducible model that mimics in all the complexity the pathological microenvironment. Specifically, the will to improve the overall survival of young patients affected by rhabdomyosarcoma compels researchers to develop new models resembling the multifaceted environment of the pathology to deeply study the disease under novel and different aspects. To this end, we developed a decellularization protocol for alveolar rhabdomyosarcoma (ARMS) able to maintain the three-dimensional structure. The attained extracellular matrix (ECM) can be used as 3D in vitro model suitable to both recapitulate the in vivo cancer microenvironment, and also for drug testing. Here, we first describe a detergent-enzymatic method and then we analyze the decellularization efficiency and the scaffold proteins.
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http://dx.doi.org/10.1007/7651_2017_45DOI Listing
February 2019

Diverging Concepts and Novel Perspectives in Regenerative Medicine.

Int J Mol Sci 2017 May 9;18(5). Epub 2017 May 9.

Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.

Regenerative medicine has rapidly evolved, due to progress in cell and molecular biology allowing the isolation, characterization, expansion, and engineering of cells as therapeutic tools. Despite past limited success in the clinical translation of several promising preclinical results, this novel field is now entering a phase of renewed confidence and productivity, marked by the commercialization of the first cell therapy products. Ongoing issues in the field include the use of pluripotent vs. somatic and of allogenic vs. autologous stem cells. Moreover, the recognition that several of the observed beneficial effects of cell therapy are not due to integration of the transplanted cells, but rather to paracrine signals released by the exogenous cells, is generating new therapeutic perspectives in the field. Somatic stem cells are outperforming embryonic and induced pluripotent stem cells in clinical applications, mainly because of their more favorable safety profile. Presently, both autologous and allogeneic somatic stem cells seem to be equally safe and effective under several different conditions. Recognition that a number of therapeutic effects of transplanted cells are mediated by paracrine signals, and that such signals can be found in extracellular vesicles isolated from culture media, opens novel therapeutic perspectives in the field of regenerative medicine.
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http://dx.doi.org/10.3390/ijms18051021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454934PMC
May 2017

The Immunoregulatory Activity of Mesenchymal Stem Cells: 'State of Art' and 'Future Avenues'.

Curr Med Chem 2016 ;23(27):3014-3024

Infectivology and Clinical Trials Area, Children's Hospital Bambino Gesù, 00146, Rome, Italy.

Mesenchymal stem cells are spindle-like plastic adherent multipotent cells that can differentiate into multiple specialized cell types including osteoblasts, chondrocytes and adipocytes. They were isolated from many tissues and organs and they contribute to the maintenance and regeneration of several tissues. Besides their ability of self-renewal, they have recently been shown to have a clinical/therapeutic potential particularly for their immunomodulatory properties. Indeed recent studies suggested a potential application of MSCs for the treatment of experimental autoimmune disorders. It was demonstrated that their effects are in part mediated by the release of soluble factors or extracellular vesicles, including exosomes and microvesicles, stimulating or inhibiting target cells. This review will describe the secretome of MSCs, pointing the attention on the components relevant for their immunodulatory activities.
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http://dx.doi.org/10.2174/0929867323666160627112827DOI Listing
February 2017

New Perspectives in Glioblastoma: Nanoparticles-based Approaches.

Curr Cancer Drug Targets 2017 ;17(3):203-220

Multi-Factorial Disease and Complex Phenotype Research Area, Bambino Gesu Children's Hospital, IRCCS, Viale di San Paolo 15, 00146, Rome, Italy.

Glioblastoma multiforme represents one of the most aggressive tumor of central nervous system. Current therapy includes surgery, radiation and chemotherapy. These treatments are rarely curative and glioma are associated with a poor prognosis. Nanomedicine represents the most innovative branch of medicine since many studies demonstrated great advantage in the diagnosis and therapy of several diseases. In this review we will summarize the results obtained by the use of nanoparticles and extracellular vesicles in glioblastoma. A great interest is raising from these studies that underlined the efficacy and specificity of this treatment for glioma, reducing side-effects associated with conventional therapies.
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http://dx.doi.org/10.2174/1568009616666160813190732DOI Listing
October 2017

Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice.

PLoS One 2016 26;11(5):e0156039. Epub 2016 May 26.

Institute of Research for Food Safety & Health (IRC_FSH), Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881894PMC
July 2017

Extracellular Vesicles in Physiology, Pathology, and Therapy of the Immune and Central Nervous System, with Focus on Extracellular Vesicles Derived from Mesenchymal Stem Cells as Therapeutic Tools.

Front Cell Neurosci 2016 2;10:109. Epub 2016 May 2.

NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences Warsaw, Poland.

Extracellular vesicles (EVs) are membrane-surrounded structures released by most cell types. They are characterized by a specific set of proteins, lipids and nucleic acids. EVs have been recognized as potent vehicles of intercellular communication to transmit biological signals between cells. In addition, pathophysiological roles of EVs in conditions like cancer, infectious diseases and neurodegenerative disorders are well established. In recent years focus has been shifted on therapeutic use of stem cell derived-EVs. Use of stem cell derived-EVs present distinct advantage over the whole stem cells as EVs do not replicate and after intravenous administration, they are less likely to trap inside the lungs. From the therapeutic perspective, the most promising cellular sources of EVs are mesenchymal stem cells (MSCs), which are easy to obtain and maintain. Therapeutic activity of MSCs has been shown in numerous animal models and the beneficial paracrine effect of MSCs may be mediated by EVs. The various components of MSC derived-EVs such as proteins, lipids, and RNA might play a specific therapeutic role. In this review, we characterize the role of EVs in immune and central nervous system (CNS); present evidences for defective signaling of these vesicles in neurodegeneration and therapeutic role of EVs in CNS.
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http://dx.doi.org/10.3389/fncel.2016.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852177PMC
May 2016

A waterborn zoonotic helminthiase in an Italian diver: a case report of a cutaneous Sparganum infection and a review of European cases.

Pathog Glob Health 2015 9;109(8):383-6. Epub 2016 Jan 9.

1 Unit of Parasitology, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy.

Many waterborne helminthes are opportunistic parasites that can travel directly from animals to man and may contain forms capable of penetrating the skin. Among these, Sparganum is the pseudophyllidean tapeworm that belongs to the genus Spirometra, which is responsible for parasitic zoonosis; it is rarely detected in Europe and is caused by the plerocercoid infective larva. Thus far, only six cases of cutaneous and ocular sparganosis have been reported in Europe; two and four cases have occurred in France and Italy, respectively. Herein, we describe a new case of sparganosis in Italy that affected a male diver who presented to the Bambino Gesù Children's Hospital of Rome. The patient's skin biopsy was submitted to the Parasitology department who, in consultation with Pathology, concluded that the morphologic and microscopic findings were those of Sparganum spp. larvae. The patient recovered following a single dose of 600 mg praziquantel.
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http://dx.doi.org/10.1080/20477724.2015.1123901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809237PMC
October 2016

A Simple and Effective Mass Spectrometric Approach to Identify the Adulteration of the Mediterranean Diet Component Extra-Virgin Olive Oil with Corn Oil.

Int J Mol Sci 2015 Sep 1;16(9):20896-912. Epub 2015 Sep 1.

Parasitology Unit, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Piazza Sant'Onofrio 4, Rome 00165, Italy.

Extra virgin olive oil (EVOO) with its nutraceutical characteristics substantially contributes as a major nutrient to the health benefit of the Mediterranean diet. Unfortunately, the adulteration of EVOO with less expensive oils (e.g., peanut and corn oils), has become one of the biggest source of agricultural fraud in the European Union, with important health implications for consumers, mainly due to the introduction of seed oil-derived allergens causing, especially in children, severe food allergy phenomena. In this regard, revealing adulterations of EVOO is of fundamental importance for health care and prevention reasons, especially in children. To this aim, effective analytical methods to assess EVOO purity are necessary. Here, we propose a simple, rapid, robust and very sensitive method for non-specialized mass spectrometric laboratory, based on the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) coupled to unsupervised hierarchical clustering (UHC), principal component (PCA) and Pearson's correlation analyses, to reveal corn oil (CO) adulterations in EVOO at very low levels (down to 0.5%).
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http://dx.doi.org/10.3390/ijms160920896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613234PMC
September 2015

The Use of Mesenchymal Stem Cells for the Treatment of Autoimmunity: From Animals Models to Human Disease.

Curr Drug Targets 2016 ;17(2):229-38

Immunology and Pharmacotherapy Research Area, Bambino Gesù Children's Hospital, Viale S. Paolo 15, 00146 Rome, Italy.

Mesenchymal stem cells are multipotent progenitors able to differentiate into osteoblasts, chondrocytes and adipocytes. These cells also exhibit remarkable immune regulatory properties, which stimulated both in vitro and in vivo experimental studies to unravel the underlying mechanisms as well as extensive clinical applications. Here, we describe the effects of MSCs on immune cells and their application in animal models as well as in clinical trials of autoimmune diseases. It should be pointed out that, while the number of clinical applications is increasing steadily, results should be interpreted with caution, in order to avoid rising false expectations. Major issues conditioning clinical application are the heterogeneity of MSCs and their unpredictable behavior following therapeutic administration. However, increasing knowledge on the interaction between exogenous cell and host tissue, as well as some encouraging clinical observations suggest that the therapeutic applications of MSCs will be further expanded on firmer grounds in the near future.
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http://dx.doi.org/10.2174/1389450116666150722140633DOI Listing
October 2016

Gut microbiota-derived outer membrane vesicles: under-recognized major players in health and disease?

Discov Med 2015 May;19(106):343-8

Department of Women's and Children's Health, University of Padova, 35128 Padova, Italy.

The role of gut microbiota both in human health and in disease is the subject of intense investigation. The interactions between gut microbiota and the host involve a complex network of metabolic pathways and of biologically active molecules secreted by intestinal bacteria, some of which are packed into nanoparticles known as outer membrane vesicles (OMVs). OMVs can enter the systemic circulation and be delivered to different organs including the brain, eliciting a variety of immunological and metabolic responses. The resulting acute and chronic effects are largely unknown. However, recent studies suggest that OMVs could play a critical role in immune homeostasis and in acute inflammatory reactions. Moreover, the "leaky gut" hypothesis has recently emphasized the role of the brain-gut axis in the pathogenesis of major depressive disorders, pointing to the importance of bacteria and of bacterial products delivered into the circulation in eliciting the low-grade inflammatory response associated with this syndrome. Interestingly, experimental evidence suggests that OMVs can also affect the permeability of the blood-brain barrier. This review also highlights the importance of investigating possible influences of OMVs on the development of the immune system.
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May 2015

Biomarkers of Alzheimer disease, insulin resistance, and obesity in childhood.

Pediatrics 2015 Jun 11;135(6):1074-81. Epub 2015 May 11.

Research Unit for Multi-factorial Diseases, Scientific Directorate, and

Objective: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid β-protein 42 (Aβ42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI.

Methods: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent β-cell function (HOMA-β) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated.

Results: Obese adolescents had values of Aβ42 higher than overweight and normal-weight peers (190.2 ± 9.16 vs 125.9 ± 7.38 vs 129.5 ± 7.65 pg/mL; P < .0001) as well as higher levels of PSEN1 (2.34 ± 0.20 vs 1.95 ± 0.20 vs 1.65 ± 0.26 ng/mL; P < .0001). Concentrations of Aβ42 were significantly correlated with BMI (ρ = 0.262; P < .0001), HOMA-IR (ρ = 0.261; P < .0001) and QUICKI (ρ = -0.220; P < .0001). PSEN1 levels were correlated with BMI (ρ = 0.248; P < .0001), HOMA-IR (ρ = 0.242; P < .0001), and QUICKI (ρ = -0.256; P < .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein.

Conclusion: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD.
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http://dx.doi.org/10.1542/peds.2014-2391DOI Listing
June 2015