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4. Supplementary material from Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression

Author

Baglio, S. Rubina, primary, Lagerweij, Tonny, primary, Pérez-Lanzón, Maria, primary, Ho, Xuan Dung, primary, Léveillé, Nicolas, primary, Melo, Sonia A., primary, Cleton-Jansen, Anne-Marie, primary, Jordanova, Ekaterina S., primary, Roncuzzi, Laura, primary, Greco, Michelina, primary, van Eijndhoven, Monique A.J., primary, Grisendi, Giulia, primary, Dominici, Massimo, primary, Bonafede, Roberta, primary, Lougheed, Sinead M., primary, de Gruijl, Tanja D., primary, Zini, Nicoletta, primary, Cervo, Silvia, primary, Steffan, Agostino, primary, Canzonieri, Vincenzo, primary, Martson, Aare, primary, Maasalu, Katre, primary, Köks, Sulev, primary, Wurdinger, Tom, primary, Baldini, Nicola, primary, and Pegtel, D. Michiel, primary

Published
2023
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8. List of Contributors

Author

Abbas, Ghulam, primary, Adamowicz, Piotr, additional, Adan, Ana, additional, Agay, Nirit, additional, Al-Halabí, S., additional, Altun, Hatice, additional, Amini, Maryam, additional, Andersen, Monica L., additional, Andreassen, Cecilie Schou, additional, Anthony, James C., additional, Ardakani, Yalda Hosseinzadeh, additional, Aromatario, Mariarosaria, additional, Arun, Priti, additional, Atik, Anzari, additional, Atti, Anna Rita, additional, Baird, Alison L., additional, Balconi, Michela, additional, Ballóková, Anna Lukačišinová, additional, Bascarán, M.T., additional, Battagliese, Gemma, additional, Benaiges, Irina, additional, Bergen-Cico, Dessa, additional, Berrettini, Wade H., additional, Berro, Laís F., additional, Bertol, Elisabetta, additional, Bian, Jin-Song, additional, Bobes-Bascarán, M.T., additional, Bobes, J., additional, Bocarsly, Miriam E., additional, Bocca, Marie-Laure, additional, Bonafede, Roberta, additional, Borroto-Escuela, Dasiel O., additional, Bottoni, Edoardo, additional, Bousoño, M., additional, Bowen, Michael T., additional, Bramanti, Placido, additional, Buck, Kari J., additional, Buisman-Pijlman, Femke T.A., additional, Büttner, Andreas, additional, Calabrò, Rocco S., additional, Çamsari, Ulaş M., additional, Cappelletti, Simone, additional, Carbo-Gas, María, additional, Casadio, Paola, additional, Casadó-Anguera, Verònica, additional, Casadó, Vicent, additional, Ceccanti, Mauro, additional, Chang, Yong-Yuan, additional, Chang, Young-Tae, additional, Chiu, Meng-Chun, additional, Chiu, Nan-Ying, additional, Cho, Zang-Hee, additional, Chung, Yemina, additional, Ciallella, Costantino, additional, Cinosi, Eduardo, additional, Conigrave, Katherine M., additional, Coogan, Andrew N., additional, Coppola, Maurizio, additional, Cortés, Antoni, additional, Costa, Giulia, additional, Cox, Stephen, additional, Dafny, Nachum, additional, Das, Subhash, additional, Davis, Jonathan M., additional, De Matteo, Robert, additional, Demetrovics, Zsolt, additional, Demirkol, Apo, additional, Denovan-Wright, Eileen M., additional, di Giannantonio, Massimo, additional, Edgunlu, Tuba, additional, Elliott, Simon, additional, Enman, Nicole M., additional, Ensafi, Ali A., additional, Faccini, Marco, additional, Falls, Brian A., additional, Fang, Chiu-Ping, additional, Fan, Lir-Wan, additional, Farooq, Ahsana Dar, additional, Feingold, Daniel, additional, Ferraro, Luca, additional, Fialová, Daniela, additional, Filip, Malgorzata, additional, Findikli, Ebru, additional, Finocchiaro, Roberta, additional, Fiore, Paola A., additional, Font-Mayolas, Sílvia, additional, Fox, Jonah, additional, Fragou, Domniki, additional, Fu, Qiang, additional, Fuxe, Kjell, additional, Gahr, Maximilian, additional, García-Portilla, M.P., additional, George, Preeta, additional, Gil-Miravet, Isis, additional, Gorwood, Philip, additional, Gras, Maria Eugènia, additional, Gravielle, María Clara, additional, Griffiths, Mark D., additional, Haber, Paul S., additional, Hadad, Natalie A., additional, Hall, F. Scott, additional, Han, Doug Hyun, additional, Harding, Richard, additional, Hashmi, Rida, additional, Hassanian-Moghaddam, Hossein, additional, Hernández-Serrano, Olga, additional, Herrmann, Evan S., additional, Herzog, Thaddeus A., additional, Heydari-Bafrooei, Esmaeil, additional, Hirota, Kiichi, additional, Ho, Ming-Chou, additional, Howell, Leonard L., additional, Hsu, Wen-Yu, additional, Huang, Chieh-Liang, additional, Hughes, Robert N., additional, Hymel, Kristen A., additional, Hyun, Gi Jung, additional, Inoue, Koichi, additional, Islam, M. Mofizul, additional, Jamali, Bardia, additional, Jerzemowska, Grażyna, additional, Job, Martin O., additional, Johannessen, Jan Olav, additional, Johansen, Helen J., additional, Johnson, Matthew W., additional, Johnson, Patrick S., additional, Kang, Chang-Ki, additional, Karakaş-Çelik, Sevim, additional, Kharas, Natasha, additional, Kim, Young-Bo, additional, Knackstedt, Lori A., additional, Kokki, Hannu, additional, Kokki, Merja, additional, Konopka, Anna, additional, Kopcza, Kathleen, additional, Kouvelas, Dimitrios, additional, Kovatsi, Leda, additional, Kruse, Lauren C., additional, Lai, Chien-Wen, additional, Lapeyre-Mestre, Maryse, additional, Lauterbach, Edward C., additional, Le Strat, Yann, additional, Lee, Chen-Yi, additional, Lejoyeux, Michel, additional, Leone, Roberto, additional, Lev-Ran, Shaul, additional, Li, Ren-Hau, additional, Liang, Willmann, additional, Liu, Jiajun, additional, Liu, Ling-Jun, additional, Liu, Liwei, additional, Liu, Sheng-Wen, additional, Liu, Yu-Li, additional, Li, Zia, additional, Lobo, Daniela S.S., additional, Lou, Jingsheng, additional, Luigi Picci, Rocco, additional, Lupi, Matteo, additional, Lutz, Brianna M., additional, MacClurg, Kendra, additional, Magro, Lara, additional, Manchia, Mirko, additional, Maraz, Aniko, additional, Martin-Fardon, Rémi, additional, Martinotti, Giovanni, additional, Matzeu, Alessandra, additional, McLaughlin, Jay P., additional, McRae, Ian S., additional, Meyerhoff, Dieter J., additional, Miquel, Marta, additional, Mondola, Raffaella, additional, Moore, Robert, additional, Morelli, Micaela, additional, Moreno, Estefanía, additional, Mori, Tomohisa, additional, Murnion, Bridin, additional, Murphy, Kelle L., additional, Nagpure, Bhushan Vijay, additional, Naro, Antonino, additional, Neutel, C. Ineke, additional, Nielsen, Suzanne, additional, Nomura, Motoo, additional, Oliva, Francesco, additional, Olive, M. Foster, additional, Olivoni, Deanna, additional, Ouyang, Qin, additional, Pallesen, Ståle, additional, Palmaro, Aurore, additional, Papazisis, Georgios, additional, Paris, Jason J., additional, Park, Chan-A, additional, Park, Jeong Ha, additional, Pełka Wysiecka, Justyna, additional, Pearson-Dennett, Verity, additional, Phillips, Daniel E., additional, Pinna, Martina, additional, Plener, Paul L., additional, Ramoz, Nicolas, additional, Renshaw, Perry F., additional, Reyes, Beverly A.S., additional, Rivera, Alicia, additional, Robinson, Susan E., additional, Romolo, Francesco S., additional, Roohbakhsh, Ali, additional, Rouini, Mohammadreza, additional, Roussin, Anne, additional, Roussotte, Florence F., additional, Saiz, P.A., additional, Samochowiec, J., additional, Sanchis-Segura, Carla, additional, Santacroce, Rita, additional, Sato-Bigbee, Carmen, additional, Sayin, H. Umit, additional, Searles Quick, Veronica B., additional, Şenormanci, Ömer, additional, Seseña, Emmanuel, additional, Shamsizadeh, Ali, additional, Sheikholeslami, Behjat, additional, Shen, Bin, additional, Shibasaki, Masahiro, additional, Shillcutt, Samuel D., additional, Simola, Nicola, additional, Singh, Rachana, additional, Soraisham, Amuchou Singh, additional, Soto, Enrique, additional, Soyka, Michael, additional, Stepens, Ainars, additional, Sullman, Mark J.M., additional, Sun, Linlin, additional, Suzuki, Tsutomu, additional, Szabo, Attila, additional, Taba, Pille, additional, Tang, Hong Chai, additional, Tang, Tze-Chun, additional, Tao, Yuan-Xiang, additional, ten Velden Hegelstad, Wenche, additional, Thome, Johannes, additional, Thompson, Paul M., additional, Tien, Lu-Tai, additional, Tietz, Elizabeth I., additional, Todd, Gabrielle, additional, Tolcos, Mary, additional, Torkamanian, Meshkat, additional, Tsung, Jieh-Hen, additional, Tufik, Sergio, additional, Ullah, Mafaz, additional, Vaiano, Fabio, additional, Van Bockstaele, Elisabeth J., additional, Vandrey, Ryan, additional, Vazquez-Sanroman, Dolores, additional, Vega, Rosario, additional, Vitali, Mario, additional, Wai, Maria S.M., additional, Wang, Junmei, additional, Wang, Lirong, additional, Wang, Sheng-Chang, additional, Weibell, Melissa A., additional, Weinstein, Aviv, additional, White, Jason M., additional, Wilcox, Robert A., additional, Wilson, Hester, additional, Wouldes, Trecia A., additional, Wydra, Karolina, additional, Xie, Xiang-Qun, additional, Xie, Zhaojun, additional, Xi, Zheng-Xiong, additional, Xu, Wang, additional, Yang, Hai-Yu, additional, Yang, Peng, additional, Yechiam, Eldad, additional, Yew, David T., additional, Yong, Andrew W.S., additional, Zamani, Nasim, additional, Zoellner, Hans, additional, and Zuba, Dariusz, additional

Published
2016
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13. Nanovesicles from adipose-derived mesenchymal stem cells inhibit T lymphocyte trafficking and ameliorate chronic experimental autoimmune encephalomyelitis

Author

Farinazzo, Alessia, primary, Angiari, Stefano, additional, Turano, Ermanna, additional, Bistaffa, Edoardo, additional, Dusi, Silvia, additional, Ruggieri, Serena, additional, Bonafede, Roberta, additional, Mariotti, Raffaella, additional, Constantin, Gabriela, additional, and Bonetti, Bruno, additional

Published
2018
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15. MRI reveals therapeutical efficacy of stem cells: An experimental study on the SOD1(G93A) animal model

Author

Bontempi, Pietro, Busato, Alice, Bonafede, Roberta, Schiaffino, Lorenzo, Scambi, Ilaria, Sbarbati, Andrea, Mariotti, Raffaella, and Marzola, Pasquina

Subjects
Male, amyotrophic lateral sclerosis, MRI, SOD1(G93A), mesenchymal stem cells, voxel-based morphometry, Mice, Superoxide Dismutase-1, Image Processing, Computer-Assisted, Animals, Humans, Transgenes, Promoter Regions, Genetic, Behavior, Animal, Superoxide Dismutase, Stem Cells, Brain, Magnetic Resonance Imaging, Disease Models, Animal, Diffusion Tensor Imaging, Phenotype, Disease Progression, Anisotropy, Female, Biomarkers, Brain Stem, Stem Cell Transplantation
Abstract

The first part of the experiment identifies and validates MRI biomarkers distinctive of the disease progression in the transgenic superoxide dismutase gene (SOD1(G93A)) animal model. The second part assesses the efficacy of a mesenchymal stem cell-based therapy through the MRI biomarkers previously defined.The first part identifies MRI differences between SOD1(G93A) and healthy mice. The second part of the experiment follows the disease evolution of stem cell-treated and non-stem-cell treated SOD1(G93A) mice. The analysis focused on voxel-based morphometry and T2 mapping on the brain tissues, and T2-weighted imaging and diffusion tensor imaging (DTI) on the hind limbs.Comparing diseased mice to healthy control revealed gray matter alterations in the brainstem area, accompanied by increased T2 relaxation time. Differences in muscle volume, muscle signal intensity, fractional anisotropy, axial diffusivity, and radial diffusivity were measured in the hind limbs. In the comparison between stem cell-treated mice and nontreated ones, differences in muscle volume, muscle signal intensity, and DTI-derived maps were found.MRI-derived biomarkers can be used to identify differences between stem cell-treated and nontreated SOD1(G93A) mice. Magn Reson Med 79:459-469, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Published
2016

16. Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression

Author

Baglio, S. Rubina, primary, Lagerweij, Tonny, additional, Pérez-Lanzón, Maria, additional, Ho, Xuan Dung, additional, Léveillé, Nicolas, additional, Melo, Sonia A., additional, Cleton-Jansen, Anne-Marie, additional, Jordanova, Ekaterina S., additional, Roncuzzi, Laura, additional, Greco, Michelina, additional, van Eijndhoven, Monique A.J., additional, Grisendi, Giulia, additional, Dominici, Massimo, additional, Bonafede, Roberta, additional, Lougheed, Sinead M., additional, de Gruijl, Tanja D., additional, Zini, Nicoletta, additional, Cervo, Silvia, additional, Steffan, Agostino, additional, Canzonieri, Vincenzo, additional, Martson, Aare, additional, Maasalu, Katre, additional, Köks, Sulev, additional, Wurdinger, Tom, additional, Baldini, Nicola, additional, and Pegtel, D. Michiel, additional

Published
2017
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20. Lanthanide-doped CaF2 and SrF2 nanoparticles for biomedical applications: in vivo and in vitro experimental studies

Author

Portioli, Corinne, Pedroni, Marco, Benati, Donatella, Dusi, Stefano, Donini, Marta, Mariotti, Raffaella, Bonafede, Roberta, Perbellini, Luigi, Cerpelloni, Marzia, Speghini, Adolfo, and Bentivoglio, Marina

Subjects
Biodistribution, inorganic chemicals, Lanthanide ions, Nanoparticles, Cell viability, technology, industry, and agriculture
Abstract

Among the wide range of nanoparticles (NPs) studied for diagnostic and therapeutic applications lanthanide-doped nanosystems have raised special interest [1]. Their very small dimension (10 nm) and upconversion emission property have increased the range of their applications from contrast agent probes in bioimaging to drug delivery systems [2,3]. Here, the cytotoxicity of rare earth (Yb and Er)-doped CaF2 and SrF2 NPs has been investigated both in vitro and in vivo. In vitro studies have been conducted in a motoneuron cell line as model of neuronal interaction, and in a line of human dendritic cells which play a key role in the immune response. In the motoneuron cell line, a weak response was observed at early time points while the cell viability showed an increment, except for the highest concentration of lanthanide- doped NPs. The levels of cytokines released from human dendritic cells were low and dose-dependent. The NP biodistribution was investigated after a single peripheral administration in mice. Aggregates of NPs were shown, with different techniques, mostly in peripheral organs (spleen and liver) after one day. A limited penetration of both CaF2 and SrF2 NPs was seen in the brain parenchyma, associated with a mild astrocytic activation. Since the present in vitro findings indicate that lanthanide- doped NPs are safe, and the in vivo data show that they can enter the brain parenchyma crossing the blood-brain barrier, these NPs may represent promising tools for diagnostic and therapeutical applications., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015

Published
2015
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21. Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: a new method to obtain labeled exosomes

Author

Busato,Alice, Bonafede,Roberta, Bontempi,Pietro, Scambi,Ilaria, Schiaffino,Lorenzo, Benati,Donatella, Malatesta,Manuela, Sbarbati,Andrea, Marzola,Pasquina, Mariotti,Raffaella, Busato,Alice, Bonafede,Roberta, Bontempi,Pietro, Scambi,Ilaria, Schiaffino,Lorenzo, Benati,Donatella, Malatesta,Manuela, Sbarbati,Andrea, Marzola,Pasquina, and Mariotti,Raffaella

Abstract

Alice Busato,1,* Roberta Bonafede,1,* Pietro Bontempi,2 Ilaria Scambi,1 Lorenzo Schiaffino,1 Donatella Benati,1 Manuela Malatesta,1 Andrea Sbarbati,1 Pasquina Marzola,3 Raffaella Mariotti1 1Department of Neurosciences, Biomedicine and Movement Sciences, School of Medicine, 2Department of Biotechnology, 3Department of Computer Science, University of Verona, Verona, Italy *These authors contributed equally to this work Purpose: Recent findings indicate that the beneficial effects of adipose stem cells (ASCs), reported in several neurodegenerative experimental models, could be due to their paracrine activity mediated by the release of exosomes. The aim of this study was the development and validation of an innovative exosome-labeling protocol that allows to visualize them with magnetic resonance imaging (MRI).Materials and methods: At first, ASCs were labeled using ultrasmall superparamagnetic iron oxide nanoparticles (USPIO, 4–6 nm), and optimal parameters to label ASCs in terms of cell viability, labeling efficiency, iron content, and magnetic resonance (MR) image contrast were investigated. Exosomes were then isolated from labeled ASCs using a standard isolation protocol. The efficiency of exosome labeling was assessed by acquiring MR images in vitro and in vivo as well as by determining their iron content. Transmission electron microscopy images and histological analysis were performed to validate the results obtained.Results: By using optimized experimental parameters for ASC labeling (200 µg Fe/mL of USPIO and 72 hours of incubation), it was possible to label 100% of the cells, while their viability remained comparable to unlabeled cells; the detection limit of MR images was of 102 and 2.5×103 ASCs in vitro and in vivo, respectively. Exosomes isolated from previously labeled ASCs retain nanoparticles, as demonstrated by transmission electron microscopy images. The detection limit by MRI was 3 &

Published
2016

22. Citrate-stabilized lanthanide-doped nanoparticles: brain penetration and interaction with immune cells and neurons

Author

Portioli, Corinne, primary, Pedroni, Marco, additional, Benati, Donatella, additional, Donini, Marta, additional, Bonafede, Roberta, additional, Mariotti, Raffaella, additional, Perbellini, Luigi, additional, Cerpelloni, Marzia, additional, Dusi, Stefano, additional, Speghini, Adolfo, additional, and Bentivoglio, Marina, additional

Published
2016
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23. Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: a new method to obtain labeled exosomes

Author

Marzola, Pasquina, primary, Busato, Alice, additional, Bonafede, Roberta, additional, Bontempi, Pietro, additional, Scambi, Ilaria, additional, Schiaffino, Lorenzo, additional, Benati, Donatella, additional, Malatesta, Manuela, additional, Sbarbati, Andrea, additional, and Mariotti, Raffaella, additional

Published
2016
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25. The Anti-Apoptotic Effect of ASC-Exosomes in an In Vitro ALS Model and Their Proteomic Analysis.

Author

Bonafede, Roberta, Brandi, Jessica, Manfredi, Marcello, Scambi, Ilaria, Schiaffino, Lorenzo, Merigo, Flavia, Turano, Ermanna, Bonetti, Bruno, Marengo, Emilio, Cecconi, Daniela, and Mariotti, Raffaella

Subjects
*EXOSOMES, *AMYOTROPHIC lateral sclerosis, *PROTEOMICS, *BCL-2 proteins, *FAT cells, *STEM cell treatment
Abstract

Stem cell therapy represents a promising approach in the treatment of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). The beneficial effect of stem cells is exerted by paracrine mediators, as exosomes, suggesting a possible potential use of these extracellular vesicles as non-cell based therapy. We demonstrated that exosomes isolated from adipose stem cells (ASC) display a neuroprotective role in an in vitro model of ALS. Moreover, the internalization of ASC-exosomes by the cells was shown and the molecules and the mechanisms by which exosomes could exert their beneficial effect were addressed. We performed for the first time a comprehensive proteomic analysis of exosomes derived from murine ASC. We identified a total of 189 proteins and the shotgun proteomics analysis revealed that the exosomal proteins are mainly involved in cell adhesion and negative regulation of the apoptotic process. We correlated the protein content to the anti-apoptotic effect of exosomes observing a downregulation of pro-apoptotic proteins Bax and cleaved caspase-3 and upregulation of anti-apoptotic protein Bcl-2 α, in an in vitro model of ALS after cell treatment with exosomes. Overall, this study shows the neuroprotective effect of ASC-exosomes after their internalization and their global protein profile, that could be useful to understand how exosomes act, demonstrating that they can be employed as therapy in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Published
2019
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26. Evaluation of the effect of exosomes isolated from stem cells in in vivo model of ALS.

Author

Mariotti, Raffaella, Bonafede, Roberta, Buoso, Chiara, Scambi, Ilaria, and Schiaffino, Lorenzo

Subjects
*EXOSOMES, *STEM cells, *AMYOTROPHIC lateral sclerosis
Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease: its peculiarity is represented by the progressive loss of the upper and lower motor neurons (LMNs) at the spinal or bulbar level. The ALS sporadic form affects 90-95% of the cases, while the remaining 5-10% are familiar. The superoxide dismutase 1 (SOD1) gene was the first identified gene to be correlated with familiar form. An effective treatment is currently not available; some drugs seem to modestly slow down the disease progression, influencing minimally the survival of the patients. A promising therapeutic approach for ALS is represented by mesenchymal stem cells, in particular, adipose stem cells (ASC). The beneficial effect of these cells seems to be due to a paracrine action via the release of exosomes (ASC-exosomes). Exosomes are small vesicles (30-100 nm) containing lipids, proteins, and nucleic acids related to the type of cell that secretes them. Exosomes, through the release of their content, enhance the repair of the damaged area and could be used as a novel cell-free therapeutic approach, avoiding all the risks associated with the use of cells, there are also evidence in in vitro model of ALS. On this basis we wanted to assess the efficacy of ASC-exosomes in in vivo model of ALS, the SOD1(G93A) mice. We injected ASC-exosomes intravenously, every four days, from the onset of the animals until the end stage. The progression of disease was monitored through the behavioural motor test and the evaluation of neurological score. Despite we did not observe a postponement of the treated animal's survival, we show that the treatment delays the symptoms progression of the disease of the treated animals compared to the control group. Moreover, the evaluation of the motoneurons number and the inflammatory state, through the assessment of astrocytes and microglia activation, is ongoing. In addition, in order to identify some of the molecular pathways by which exosomes could exert the neuroprotective effect on motoneurons, we performed the protein content characterization of ASC-exosomes. These data suggest that ASC-exosomes exert a neuroprotective role in in vivo model of ALS, underlining a possible therapeutic use of exosomes in this neurodegenerative disease and also suggest molecules that could be responsible for these neuroprotective effect in order to potentiate their effect in the future. [ABSTRACT FROM AUTHOR]

Published
2018

27. Synaptic stripping and MHC class I expression in the facial motor nucleus of ALS mice.

Author

Mariotti, Raffaella, Kassa, Roman M., Bonafede, Roberta, Boschi, Federico, Malatesta, Manuela, and Bentivoglio, Marina

Subjects
LABORATORY mice, ANIMAL models of amyotrophic lateral sclerosis, MOTOR neuron diseases
Abstract

Pathogenetic mechanisms involved in the fatal, still incurable neurodegenerative disease amyotrophic lateral sclerosis (ALS), characterized by progressive motoneuron death, await full clarification, important for the development of new therapeutic approaches. In the ALS murine model provided by mutant SOD1(G93A) mice, we here investigated the presynaptic wiring of facial motoneurons in basal conditions and after facial nerve transection (a classical paradigm to examine the retrograde motoneuron response to injury), and major histocompatibility (MHC) class I antigen expression after axotomy. The study was based on fluorescent retrograde labeling of motoneurons, synaptophysin and MHC class I antigen immunostaining, electron microscopy. A significant decrease of excitatory axosomatic boutons was found in presymptomatic ALS mice compared to the wild-type (Wt) counterpart, indicating the occurrence of excitatory synapse detachment (presynaptic stripping) in mutant motoneurons. Synaptic stripping, which seems to represent a protective mechanism preserving the inhibitory input, became more marked in facial motoneurons of symptomatic ALS mice. After axotomy, synaptic stripping was consistently enhanced in ALS mice. In the axotomized facial motoneurons of Wt mice synaptic stripping was accompanied by induction of MHC class I antigens, immune molecules implicated in activity-dependent changes in synaptic connectivity and regeneration after injury. MHC class I antigen induction was instead decreased in the axotomized facial nucleus of presymptomatic ALS mice, and was very low, occurring only in glial cells, in symptomatic ALS mice. The findings demonstrate enhanced loss of excitatory presynaptic terminals, as well as a dissociation between this process and MHC class I antigen expression after injury, in motoneurons which carry a mutation committing them to death. The findings also implicate MHC class I antigen induction in glial cells surrounding ALS motoneurons in this intercellular crosstalk. [ABSTRACT FROM AUTHOR]

Published
2017

28. Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression

Author

Anne-Marie Cleton-Jansen, Vincenzo Canzonieri, Monique A. J. van Eijndhoven, Laura Roncuzzi, Sulev Kõks, Tonny Lagerweij, Nicoletta Zini, Massimo Dominici, Maria Pérez-Lanzón, Roberta Bonafede, Tanja D. de Gruijl, Silvia Cervo, Aare Märtson, Nicolas Léveillé, D. Michiel Pegtel, Nicola Baldini, Thomas Wurdinger, Xuan Dung Ho, Agostino Steffan, Katre Maasalu, Ekaterina S. Jordanova, S. Rubina Baglio, Giulia Grisendi, M. Greco, Sonia A. Melo, Sinéad M. Lougheed, Baglio, S. Rubina, Lagerweij, Tonny, Pérez-Lanzón, Maria, Ho, Xuan Dung, Léveillé, Nicola, Melo, Sonia A., Cleton-Jansen, Anne-Marie, Jordanova, Ekaterina S., Roncuzzi, Laura, Greco, Michelina, van Eijndhoven, Monique A. J., Grisendi, Giulia, Dominici, Massimo, Bonafede, Roberta, Lougheed, Sinead M., de Gruijl, Tanja D., Zini, Nicoletta, Cervo, Silvia, Steffan, Agostino, Canzonieri, Vincenzo, Martson, Aare, Maasalu, Katre, Köks, Sulev, Wurdinger, Tom, Baldini, Nicola, Pegtel, D. Michiel, Pathology, AII - Cancer immunology, CCA - Cancer biology and immunology, Neurosurgery, Obstetrics and gynaecology, Medical oncology, Medical oncology laboratory, Amsterdam Reproduction & Development (AR&D), Baglio, S Rubina, Melo, Sonia A, Jordanova, Ekaterina S, van Eijndhoven, Monique A J, Lougheed, Sinead M, de Gruijl, Tanja D, Pegtel, D Michiel, Center of Experimental and Molecular Medicine, Other departments, and ARD - Amsterdam Reproduction and Development

Subjects
0301 basic medicine, Male, Cancer Research, Pathology, Lung Neoplasms, Exosomes, Mice, Transforming Growth Factor beta, Osteosarcoma, Tissue microarray, biology, Extracellular vesicle, Gene Expression Regulation, Neoplastic, Mesenchymal Stem Cell, Oncology, EV-associated TGFβ, Cells, Recipient cells, Female, tumor extracellular vesicle (EV)–educated mesenchymal stem cells (TEMSC), Human, Signal Transduction, STAT3 Transcription Factor, musculoskeletal diseases, medicine.medical_specialty, Extracellular Vesicle, Antibodies, Monoclonal, Humanized, Extracellular Vesicles, tocilizumab, 03 medical and health sciences, Stroma, Cell Line, Tumor, medicine, Animals, Humans, Cell Proliferation, therapy, business.industry, Animal, Interleukin-6, Mesenchymal stem cell, Cancer, Mesenchymal Stem Cells, Transforming growth factor beta, Gene signature, medicine.disease, Lung Neoplasm, Exosome, Disease Models, Animal, 030104 developmental biology, Tissue Array Analysis, biology.protein, Cancer research, Cell, business, Tissue Array Analysi, osteosarcoma
Abstract

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets. Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)–educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography. Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients. Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients. Clin Cancer Res; 23(14); 3721–33. ©2017 AACR.

Published
2017
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