Ranieri Cancedda

Azienda Ospedaliera Universitaria San Martino di Genova, Genova, Liguria, Italy

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Publications (328)1387.9 Total impact

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    ABSTRACT: This manuscript reports the structural alterations occurring in mice skeleton as a consequence of the longest-term exposition (90 days) to simulated microgravity (hindlimb unloading) and hypergravity (2g) ever tested. Bone microstructural features were investigated by means of standard Cone Beam X-ray micro-CT, Synchrotron Radiation micro-CT and histology. Morphometric analysis confirmed deleterious bone architectural changes in lack of mechanical loading with a decrease of bone volume and density, while bone structure alterations caused by hypergravity were less evident. In the femurs from hypergravity-exposed mice, the head/neck cortical thickness increment was the main finding. In addition, in these mice the rate of larger trabeculae (60-75μm) was significantly increased. Interestingly, the metaphyseal plate presented a significant adaptation to gravity changes. Mineralization of cartilage and bone deposition was increased in the 2g mice, whereas an enlargement of the growth plate cartilage was observed in the hindlimb unloaded group. Indeed, the presented data confirm and reinforce the detrimental effects on bone observed in real space microgravity and reveal region-specific effects on long bones. Finally these data could represent the starting point for further long-term experimentations that can deeply investigate the bone adaptation mechanisms to different mechanical force environments. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of the Mechanical Behavior of Biomedical Materials 06/2015; 51. DOI:10.1016/j.jmbbm.2015.06.014 · 3.42 Impact Factor
  • 05/2015; 1:15002. DOI:10.1038/npjmgrav.2015.2
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    ABSTRACT: Umbilical Cord Mesenchymal Stem Cells (UC-MSC) show properties similar to Bone Marrow Mesenchymal Stem Cells (BM-MSC), though controversial data exists regarding their osteogenic potential. We prepared clinical-grade UC-MSC from Wharton's Jelly and we investigated if UC-MSC could be used as substitutes for BM-MSC in muscoloskeletal regeneration as a more readily available and functional source of MSCs. UC-MSC were loaded onto scaffolds and implanted subcutaneously (ectopically) and in critical-size calvarial defects (orthotopically) in mice. For live cell-tracking experiments, UC-MSC were first transduced with the luciferase gene. Angiogenic properties of UC-MSC were tested using the mouse metatarsal angiogenesis assay. Cell secretomes were screened for the presence of various cytokines using an array assay. Analysis of implanted scaffolds showed that UC-MSC, contrary to BM-MSC, remained detectable in the implants for 3 weeks at most and did not induce bone formation in an ectopic location. Instead, they induced a significant increase of blood vessel ingrowth. In agreement with these observations, UC-MSC conditioned medium presented a distinct and stronger pro-inflammatory/chemotactic cytokine profile than BM-MSC and a significantly enhanced angiogenic activity. When UC-MSC were orthotopically transplanted in a calvarial defect, they promoted increased bone formation as well as BM-MSC. However, at variance with BM-MSC, the new bone was deposited through the activity of stimulated host cells highlighting the importance of the microenvironment on determining cell commitment and response. Therefore, we propose, as therapy for bone lesions, the use of allogeneic UC-MSC not depositing directly bone matrix, but acting through the activation of endogenous repair mechanisms.
    Stem Cells and Development 02/2015; 24(13). DOI:10.1089/scd.2014.0490 · 4.20 Impact Factor
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    E. Patrone · M. Menini · P. Pera · M. Mastrogiacomo · R. Cancedda
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    ABSTRACT: Background Metformin is a widely used oral hypoglycemizing agent recently proposed as potential anti-cancer drug. In this study we report the antiproliferative effect of metformin treatment in a high risk neuroblastoma cell model, focusing on possible effects associated to different levels of differentiation and/or tumor initiating potential. Methods Antiproliferative and cytotoxic effects of metformin were tested in human SKNBE2 and SH-SY5Y neuroblastoma cell lines and in SKNBE2 cells in which differentiation is induced by retinoic acid treatment or stable overexpression of NDM29 non-coding RNA, both conditions characterized by a neuron-like differentiated phenotype. Results We found that metformin significantly inhibits the proliferation of NB cells, an effect that correlates with the inhibition of Akt, while AMPK activity resulted unchanged. Notably, metformin effects were modulated in a different ways by differentiating stimuli, being abolished after retinoic acid treatment but potentiated by overexpression of NDM29. Conclusion These data suggest the efficacy of metformin as neuroblastoma anticancer agent, and support the requirement of further studies on the possible role of the differentiation status on the antiproliferative effects of this drug.
    Cancer Cell International 07/2014; 14:59. DOI:10.1186/1475-2867-14-59 · 1.99 Impact Factor
  • Alessandra Ruggiu · Ranieri Cancedda
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    ABSTRACT: Bone homeostasis strongly depends on fine tuned mechanosensitive regulation signals from environmental forces into biochemical responses. Similar to the ageing process, during spaceflights an altered mechanotransduction occurs as a result of the effects of bone unloading, eventually leading to loss of functional tissue. Although spaceflights represent the best environment to investigate near-zero gravity effects, there are major limitations for setting up experimental analysis. A more feasible approach to analyse the effects of reduced mechanostimulation on the bone is represented by the ‘simulated microgravity’ experiments based on: (1) in vitro studies, involving cell cultures studies and the use of bioreactors with tissue engineering approaches; (2) in vivo studies, based on animal models; and (3) direct analysis on human beings, as in the case of the bed rest tests. At present, advanced tissue engineering methods allow investigators to recreate bone microenvironment in vitro for mechanobiology studies. This group and others have generated tissue ‘organoids’ to mimic in vitro the in vivo bone environment and to study the alteration cells can go through when subjected to unloading. Understanding the molecular mechanisms underlying the bone tissue response to mechanostimuli will help developing new strategies to prevent loss of tissue caused by altered mechanotransduction, as well as identifying new approaches for the treatment of diseases via drug testing. This review focuses on the effects of reduced gravity on bone mechanobiology by providing the up-to-date and state of the art on the available data by drawing a parallel with the suitable tissue engineering systems. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 07/2014; DOI:10.1002/term.1942 · 4.43 Impact Factor
  • Chiara Gentili · Michele Torre · Ranieri Cancedda
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    ABSTRACT: The therapeutic use of stem cells is a very promising strategy in the area of regenerative medicine. The stem cell regenerative paradigm has been mostly based on the assumption that progenitor cells play a critical role in tissue repair by their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. Preclinical and clinical skeletal studies, conducted in animal and adult series, support the use of mesenchymal stem cells (MSCs) for bone healing in critical clinical situations. These results have led to an increasing number of papers reporting the use of MSCs in adult clinical trials, whereas only few papers reported the use of these cells in pediatric skeletal disorders, probably because of unknown long-term results and long-life consequences of cellular therapy. The exponential growth of knowledge in adult MSCs could be translated and applied to pediatric disorders. Pediatric osteoarticular diseases have an enormous potential to be treated by MSCs, as severe congenital bone or local cartilage defects, not responding to conventional surgery treatment, might be successfully treated by cellular therapy. Translating basic stem cell research into routine therapies is a complex multistep process which entails the managing of the expected therapeutic benefits with the potential risks in correlation within the existing regulations. Here, we reported the state of art on the use of MSC in skeletal pediatric disorders.
    European Journal of Pediatric Surgery 06/2014; 24(03). DOI:10.1055/s-0034-1382777 · 0.98 Impact Factor
  • Valentina Ulivi · Roberta Tasso · Ranieri Cancedda · Fiorella Descalzi
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    ABSTRACT: Wound healing is achieved through distinct programmed phases: hemostasis, inflammation, mesenchymal cell proliferation and migration, and tissue remodeling. At the injury site, clot formation and platelet degranulation release cytokines, growth factors and actively participating in the healing process and regulating the migration of inflammatory cells, such as neutrophils, macrophages, and lymphocytes. We previously demonstrated that, in an inflammatory environment, PGE2 secreted by mesenchymal stem cells (MSCs) promoted the macrophage switch from a pro-inflammatory to a pro-resolving phenotype. Using an in vitro model, we here evaluated the role carried out by the two main players of the wound healing process, the platelet degranulation content mimicked by the platelet lysate (PL) and the inflammatory stimulus, on the modulation of mouse bone marrow-derived MSC paracrine activity. We demonstrated that, in MSCs, PL induced NF-kB activation, expression of COX-2, mPGE synthase and PGE2 production; in an inflammatory microenvironment, PL increased the inflammatory response and promoted the secretion of the pro-inflammatory cytokine IL-6. We assayed on mouse primary macrophages the paracrine activity of MSCs exposed to the different microenvironments and we observed that PL-treated MSC conditioned medium maintained macrophages in a pro-inflammatory state. The involved factors were GM-CSF induced by PL in MSCs and TNF-α induced by PL-MSC conditioned medium in macrophages. Our findings indicate that PL triggers an inflammatory response in MSCs and induces the secretion of factors maintaining macrophages in a pro-inflammatory state thus enhancing the initial inflammatory response to the injury, a key element in the activation of wound healing.
    Stem cells and development 04/2014; 23(16). DOI:10.1089/scd.2013.0567 · 4.20 Impact Factor
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    ABSTRACT: The effects of 3 months of spaceflight (SF), hindlimb suspension, or exposure to 2G on the characteristics of neck muscle in mice were studied. Three 8-week-old male C57BL/10J wild-type mice were exposed to microgravity on the International Space Station in mouse drawer system (MDS) project, although only one mouse returned to the Earth alive. Housing of mice in a small MDS cage (11.6 × 9.8-cm and 8.4-cm height) and/or in a regular vivarium cage was also performed as the ground controls. Furthermore, ground-based hindlimb suspension and 2G exposure by using animal centrifuge (n = 5 each group) were performed. SF-related shift of fiber phenotype from type I to II and atrophy of type I fibers were noted. Shift of fiber phenotype was related to downregulation of mitochondrial proteins and upregulation of glycolytic proteins, suggesting a shift from oxidative to glycolytic metabolism. The responses of proteins related to calcium handling, myofibrillar structure, and heat stress were also closely related to the shift of muscular properties toward fast-twitch type. Surprisingly, responses of proteins to 2G exposure and hindlimb suspension were similar to SF, although the shift of fiber types and atrophy were not statistically significant. These phenomena may be related to the behavior of mice that the relaxed posture without lifting their head up was maintained after about 2 weeks. It was suggested that inhibition of normal muscular activities associated with gravitational unloading causes significant changes in the protein expression related to metabolic and/or morphological properties in mouse neck muscle.
    01/2014; 2(1):e00183. DOI:10.1002/phy2.183
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    ABSTRACT: Computed x-ray phase contrast micro-tomography is the most valuable tool for a three dimensional (3D) and non destructive analysis of the tissue engineered bone morphology. We used a Talbot interferometer installed at SYRMEP beamline of the ELETTRA synchrotron (Trieste, Italy) for a precise 3D reconstruction of both bone and soft connective tissue, regenerated in vivo within a porous scaffold. For the first time the x-ray tomographic reconstructions have been combined with x-ray scanning micro-diffraction measurement on the same sample, in order to give an exhaustive identification of the different tissues participating to the biomineralization process. As a result, we were able to investigate in detail the different densities in the tissues, distinguishing the 3D organization of the amorphous calcium phosphate from the collagen matrix. Our experimental approach allows for a deeper understanding of the role of collagen matrix in the organic-mineral transition, which is a crucial issue for the development of new bio-inspired composites.
    Physics in Medicine and Biology 01/2014; 59(1):189-201. DOI:10.1088/0031-9155/59/1/189 · 2.92 Impact Factor
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    ABSTRACT: The present work defines a modified critical size rabbit ulna defect model for bone regeneration in which a non-resorbable barrier membrane was used to separate the radius from the ulna to create a valid model for evaluation of tissue-engineered periosteal substitutes. Eight rabbits divided into two groups were used. Critical defects (15 mm) were made in the ulna completely eliminating periosteum. For group I, defects were filled with a nanohydroxyapatite poly(ester urethane) scaffold soaked in PBS and left as such (group Ia) or wrapped with a tissue-engineered periosteal substitute (group Ib). For group II, an expanded-polytetrafluoroethylene (e-PTFE) (GORE-TEX(®)) membrane was inserted around the radius then the defects received either scaffold alone (group IIa) or scaffold wrapped with periosteal substitute (group IIb). Animals were euthanized after 12-16 weeks, and bone regeneration was evaluated by radiography, computed microtomography (μCT), and histology. In the first group, we observed formation of radio-ulnar synostosis irrespective of the treatment. This was completely eliminated upon placement of the e-PTFE (GORE-TEX(®)) membrane in the second group of animals. In conclusion, modification of the model using a non-resorbable e-PTFE membrane to isolate the ulna from the radius was a valuable addition allowing for objective evaluation of the tissue-engineered periosteal substitute.
    Frontiers in Bioengineering and Biotechnology 01/2014; 2:80. DOI:10.3389/fbioe.2014.00080
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    Physics in Medicine and Biology 01/2014; · 2.92 Impact Factor
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    Claudia Lo Sicco · Ranieri Cancedda
    Scaffolds for Tissue Engineering Biological Design, Materials, and Fabrication, Edited by Claudio Migliaresi and Antonella Motta, 01/2014: chapter Chapter 4. Principles and Biological Pathways to Tissue Regeneration: The Tissue Regenerative Niche: pages Pages 79–114; Pan Stanford Publishing., ISBN: 978-981-4463-21-8
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    ABSTRACT: We monitored bone regeneration in a tissue engineering approach. To visualize and understand the structural evolution, the samples have been measured by X-ray micro-diffraction. We find that bone tissue regeneration proceeds through a multi-step mechanism, each step providing a specific diffraction signal. The large amount of data have been classified according to their structure and associated to the process they came from combining Neural Networks algorithms with least square pattern analysis. In this way, we obtain spatial maps of the different components of the tissues visualizing the complex kinetic at the base of the bone regeneration.
    Applied Physics Letters 12/2013; 103(25):253703-253703-4. DOI:10.1063/1.4852056 · 3.52 Impact Factor
  • Sveva Bollini · Chiara Gentili · Roberta Tasso · Ranieri Cancedda
    Journal of Clinical Medicine 12/2013; 2(4):302-327. DOI:10.3390/jcm2040302
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    ABSTRACT: Lipocalin-2 (LCN2) is a protein largely expressed in many tissues, associated with different biological phenomena such as cellular differentiation, inflammation and cancer acting as a survival/apoptotic signal. We found that LCN2 was expressed during osteoblast differentiation and we generated transgenic (Tg) mice over-expressing LCN2 in bone. Tg mice were smaller and presented bone microarchitectural changes in both endochondral and intramembranous bones. In particular, Tg bones displayed a thinner layer of cortical bone and a decreased trabecular number. Osteoblast bone matrix deposition was reduced and osteoblast differentiation was slowed-down. Differences were also observed in the growth plate of young transgenic mice where chondrocyte displayed a more immature phenotype and a lower proliferation rate. In bone marrow cell cultures from transgenic mice, the number of osteoclast progenitors was increased whereas in vivo it was increased the number of mature osteoclasts expressing tartrate resistant acid phosphatase (TRAP). Finally, while osteoprotegerin (OPG) levels remained unchanged, the expression of the conventional Receptor Activator of Nuclear factor-κB Ligand (RANKL) and of the IL-6 was enhanced in Tg mice. In conclusion, we found that LCN2 plays a role in bone development and turnover having both a negative effect on bone formation, by affecting growth plate development and interfering with osteoblast differentiation, and a positive effect on bone resorption by enhancing osteoclast compartment. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 11/2013; 228(11). DOI:10.1002/jcp.24391 · 3.87 Impact Factor
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    ABSTRACT: Studies about cartilage repair in the hip and infant chondroctyes are rare. The aim of our study was to evaluate the use of infant articular hip chondrocytes for tissue engineering of scaffold-assisted cartilage grafts. Hip cartilage was obtained from five human donors (age 1-10 years). Expanded chondrocytes were cultured in polyglycolic acid (PGA)-fibrin scaffolds. De- and re-differentiation of chondrocytes was assessed by histological staining and gene expression analysis of typical chondrocytic marker genes. In vivo, cartilage matrix formation was assessed by histology after subcutaneous transplantation of chondrocyte-seeded PGA-fibrin scaffolds in immunocompromised mice. The donor tissue was heterogenous showing differentiated articular cartilage and non-differentiated tissue and considerable expression of type I and II collagens. Gene expression analysis showed repression of typical chondrocyte and/or mesenchymal marker genes during cell expansion, while markers were re-induced when expanded cells were cultured in PGA-fibrin scaffolds. Cartilage formation after subcutanuous transplantation of chondrocyte loaded PGA-fibrin scaffolds in nude mice was variable, with grafts showing resorption and host cell infiltration or formation of hyaline cartilage rich in type II collagen. Addition of human platelet rich plasma (PRP) to cartilage grafts resulted robustly in formation of hyaline-like cartilage that showed type II collagen and regions with type X collagen. These results suggest that culture of expanded and/or de-differentiated infant hip cartilage cells in PGA-fibrin scaffolds initiates chondrocyte re-differentiation. The heterogenous donor tissue containing immature chondrocytes bears the risk of cartilage repair failure in vivo, which may be possibly overcome by the addition of PRP.
    Osteoarthritis and Cartilage 10/2013; 21(12). DOI:10.1016/j.joca.2013.09.007 · 4.66 Impact Factor
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    ABSTRACT: Platelet Lysate (PL) contains a cocktail of growth factors and cytokines, which actively participates in tissue repair and its clinical application has been broadly described. The aim of this study was to assess the regenerative potential of PL for bone repair. We demonstrated that PL stimulation induces a transient increase of the inflammatory response in quiescent human osteoblasts, via NF-kB activation, COX-2 induction, PGE2 production and secretion of pro-inflammatory cytokines. Furthermore, we showed that long-term PL stimulation enhances proliferation of actively replicating osteoblasts, without affecting their differentiation potential, along with changes of cell morphology, resulting in increased cell density at confluence. In confluent resting osteoblasts, PL treatment induced resumption of proliferation, change in cell morphology and increase of cell density at confluence. A burst of PL treatment (24-h) was sufficient to trigger such processes in both conditions. These results correlated with up-regulation of the proliferative and survival pathways ERKs and Akt and with cell cycle re-activation via induction of CyclinD1 and phosphorylation of Rb, following PL stimulation. Our findings demonstrate that PL treatment results in activation and expansion of resting osteoblasts, without affecting their differentiation potential. Therefore PL represents a good therapeutic candidate in regenerative medicine for bone repair.
    Biomaterials 09/2013; 34(37). DOI:10.1016/j.biomaterials.2013.08.018 · 8.31 Impact Factor
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    ABSTRACT: Pleiotrophin (PTN) is a widespread cytokine involved in bone formation, neurite outgrowth, and angiogenesis. In skeletal muscle, PTN is upregulated during myogenesis, post-synaptic induction, and regeneration after crushing, but little is known regarding its effects on muscle function. Here, we describe the effects of PTN on the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles in mice over-expressing PTN under the control of a bone promoter. The mice were maintained in normal loading or disuse condition, induced by hindlimb unloading (HU) for 14 days. Effects of exposition to near-zero gravity during a 3-months spaceflight (SF) into the Mice Drawer System are also reported. In normal loading, PTN overexpression had no effect on muscle fiber cross-sectional area, but shifted soleus muscle toward a slower phenotype, as shown by an increased number of oxidative type 1 fibers, and increased gene expression of cytochrome c oxidase subunit IV and citrate synthase. The cytokine increased soleus and EDL capillary-to-fiber ratio. PTN overexpression did not prevent soleus muscle atrophy, slow-to-fast transition, and capillary regression induced by SF and HU. Nevertheless, PTN exerted various effects on sarcolemma ion channel expression/function and resting cytosolic Ca(2+) concentration in soleus and EDL muscles, in normal loading and after HU. In conclusion, the results show very similar effects of HU and SF on mouse soleus muscle, including activation of specific gene programs. The EDL muscle is able to counterbalance this latter, probably by activating compensatory mechanisms. The numerous effects of PTN on muscle gene expression and functional parameters demonstrate the sensitivity of muscle fibers to the cytokine. Although little benefit was found in HU muscle disuse, PTN may emerge useful in various muscle diseases, because it exerts synergetic actions on muscle fibers and vessels, which could enforce oxidative metabolism and ameliorate muscle performance.
    PLoS ONE 08/2013; 8(8):e72028. DOI:10.1371/journal.pone.0072028 · 3.23 Impact Factor

Publication Stats

14k Citations
1,387.90 Total Impact Points

Institutions

  • 2014–2015
    • Azienda Ospedaliera Universitaria San Martino di Genova
      Genova, Liguria, Italy
  • 1988–2014
    • Università degli Studi di Genova
      • • Department of Physics
      • • Dipartimento di Medicina sperimentale (DIMES)
      • • Inter-University Centre for Research on Cancer
      Genova, Liguria, Italy
  • 2007–2011
    • Polo d'Innovazione di Genomica Genetica e Biologia
      Perugia, Umbria, Italy
  • 2008
    • Society for Biomaterials
      Society Hill, New Jersey, United States
  • 2006
    • University of Geneva
      Genève, Geneva, Switzerland
  • 2005
    • IRCCS Istituto G. Gaslini
      Genova, Liguria, Italy
  • 2004
    • Centro Biotecnologie Avanzate
      Genova, Liguria, Italy
  • 2002
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
  • 2000
    • Biotecnologie Avanzate
      Napoli, Campania, Italy
  • 1988–2000
    • CRO Centro di Riferimento Oncologico di Aviano
      Aviano, Friuli Venezia Giulia, Italy
  • 1999
    • The Roslin Institute
      Edinburgh, Scotland, United Kingdom
  • 1997
    • Istituto per la Ricerca Sociale
      Milano, Lombardy, Italy
  • 1996
    • Hungarian Academy of Sciences
      • Institute of Biochemistry
      Budapeŝto, Budapest, Hungary
  • 1993
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Harvard Medical School
      • Department of Cell Biology
      Boston, Massachusetts, United States
  • 1990–1992
    • Università degli Studi di Torino
      Torino, Piedmont, Italy