57 results on '"Chiara Capelli"'
Search Results
2. A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome
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Marina Vivarelli, Manuela Colucci, Mattia Algeri, Federica Zotta, Francesco Emma, Ines L’Erario, Marco Busutti, Stefano Rota, Chiara Capelli, Martino Introna, Marta Todeschini, Federica Casiraghi, Annalisa Perna, Tobia Peracchi, Andrea De Salvo, Nadia Rubis, Franco Locatelli, Giuseppe Remuzzi, and Piero Ruggenenti
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Clinical trials ,Nephrology ,Medicine - Abstract
BACKGROUND Severe forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODS We performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow–derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTS Sixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3–6 months following BM-MSC infusionCONCLUSION Treatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3–6 months may sustain benefit.TRIAL REGISTRATION EudraCT 2016-004804-77.FUNDING AIFA Ricerca Indipendente 2016-02364623.
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- 2023
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3. Potency assays and biomarkers for cell-based advanced therapy medicinal products
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Chiara Capelli, Carolina Cuofano, Chiara Pavoni, Simona Frigerio, Daniela Lisini, Sara Nava, Michele Quaroni, Valentina Colombo, Francesco Galli, Svetlana Bezukladova, Paola Panina-Bordignon, Giuseppe Gaipa, Patrizia Comoli, Giulio Cossu, Gianvito Martino, Andrea Biondi, Martino Introna, and Josée Golay
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advanced therapy medicinal product (ATMP) ,potency ,CAR (chimeric antigen receptor) ,T cell therapy ,stem cell ,tissue regeneration ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Advanced Therapy Medicinal Products (ATMPs) based on somatic cells expanded in vitro, with or without genetic modification, is a rapidly growing area of drug development, even more so following the marketing approval of several such products. ATMPs are produced according to Good Manufacturing Practice (GMP) in authorized laboratories. Potency assays are a fundamental aspect of the quality control of the end cell products and ideally could become useful biomarkers of efficacy in vivo. Here we summarize the state of the art with regard to potency assays used for the assessment of the quality of the major ATMPs used clinic settings. We also review the data available on biomarkers that may substitute more complex functional potency tests and predict the efficacy in vivo of these cell-based drugs.
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- 2023
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4. Development and Validation of a New LC-MS/MS Bioanalytical Method for the Simultaneous Determination of Levodopa, Levodopa Methyl Ester, and Carbidopa in Human Plasma Samples
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Linda Molteni, Bruno Charlier, Viviana Izzo, Albino Coglianese, Valeria Conti, Roberto Eleopra, Roberto Cilia, Chiara Capelli, Annachiara D’Urso, and Ugo de Grazia
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levodopa ,levodopa methyl ester ,carbidopa ,Parkinson’s disease ,therapeutic drug monitoring ,liquid chromatography–mass spectrometry (LC–MS) ,Organic chemistry ,QD241-441 - Abstract
Levodopa (L-DOPA) treatment, combined with the administration of dopa-decarboxylase inhibitors (DDCIs), is still the most effective symptomatic treatment of Parkinson’s disease (PD). Although its efficacy in the early stage of the disease has been confirmed, its complex pharmacokinetics (PK) increases the variability of the intra-individual motor response, thus amplifying the risk of motor/non-motor fluctuations and dyskinesia. Moreover, it has been demonstrated that L-DOPA PK is strongly influenced by several clinical, therapeutic, and lifestyle variables (e.g., dietary proteins). L-DOPA therapeutic monitoring is therefore crucial to provide personalized therapy, hence improving drug efficacy and safety. To this aim, we have developed and validated an ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method to quantify L-DOPA, levodopa methyl ester (LDME), and the DDCI carbidopa in human plasma. The compounds were extracted by protein precipitation and samples were analyzed with a triple quadrupole mass spectrometer. The method showed good selectivity and specificity for all compounds. No carryover was observed, and dilution integrity was demonstrated. No matrix effect could be retrieved; intra-day and inter-day precision and accuracy values met the acceptance criteria. Reinjection reproducibility was assessed. The described method was successfully applied to a 45-year-old male patient to compare the pharmacokinetic behavior of an L-DOPA-based medical treatment involving commercially available Mucuna pruriens extracts and an LDME/carbidopa (100/25 mg) formulation.
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- 2023
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5. Protective Effects of Human Nonrenal and Renal Stromal Cells and Their Conditioned Media in a Rat Model of Chronic Kidney Disease
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Barbara Imberti, Domenico Cerullo, Daniela Corna, Cinzia Rota, Monica Locatelli, Anna Pezzotta, Martino Introna, Chiara Capelli, Claudia Elisa Carminati, Ton J. Rabelink, Danielle G. Leuning, Carlamaria Zoja, Marina Morigi, Giuseppe Remuzzi, Ariela Benigni, and Valerie Luyckx
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Medicine - Abstract
Mesenchymal stromal cells (MSCs) are emerging as a novel therapeutic option for limiting chronic kidney disease progression. Conditioned medium (CM) containing bioactive compounds could convey similar benefits, avoiding the potential risks of cell therapy. This study compared the efficacy of nonrenal and renal cell-based therapy with the corresponding CM in rats with renal mass reduction (RMR). Infusions of human kidney stromal cells (kPSCs) and CM-kPSCs, but not umbilical cord (uc) MSCs or CM-ucMSCs, reduced proteinuria and preserved podocyte number and nephrin expression in RMR rats. Glomerular fibrosis, microvascular rarefaction, and apoptosis were reduced by all treatments, while the peritubular microvascular loss was reduced by kPSCs and CM-kPSCs treatment only. Importantly, kPSCs and CM-kPSCs reduced NG2-positive pericytes, and all therapies reduced α-smooth muscle actin expression, indicating reduced myofibroblast expansion. Treatment with kPSCs also significantly inhibited the accumulation of ED1-positive macrophages in the renal interstitium of RMR rats. These findings demonstrate that the CM of ucMSCs and kPSCs confers similar renoprotection as the cells. kPSCs and CM-kPSCs may be superior in attenuating chronic renal injury as a cell source.
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- 2020
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6. Therapeutic potential of stromal cells of non-renal or renal origin in experimental chronic kidney disease
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Cinzia Rota, Marina Morigi, Domenico Cerullo, Martino Introna, Ornella Colpani, Daniela Corna, Chiara Capelli, Ton J. Rabelink, Danielle G. Leuning, Daniela Rottoli, Ariela Benigni, Carlamaria Zoja, and Giuseppe Remuzzi
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Mesenchymal stromal cell therapy ,Renal perivascular cells ,Conditioned medium ,Renal repair ,Chronic kidney disease ,Medicine (General) ,R5-920 ,Biochemistry ,QD415-436 - Abstract
Abstract Background Mesenchymal stromal cell (MSC)-based therapy is a promising strategy for preventing the progression of chronic kidney disease (CKD), with the potential to induce tissue regeneration. In search of the best cellular source we compared, in the rat model of adriamycin (ADR) nephropathy, the regenerative potential of human stromal cells of non-renal origin, such as bone marrow (bm) MSCs and umbilical cord (uc) MSCs, with that of newly discovered stromal cells of renal origin, the kidney perivascular cells (kPSCs) known to exhibit tissue-specific properties. Methods The therapeutic effect of repeated infusions of human bmMSCs, ucMSCs, kPSCs (1.5 × 106 cells/rats) or conditioned medium from ucMSCs was studied in athymic rats with ADR-induced nephropathy (7.9 mg/kg). The ability of the three stromal cell populations to engraft the damaged kidney was evaluated by detecting the presence of human nuclear antigenpos cells. Glomerular podocyte loss and endothelial damage, sclerotic lesions and inflammation were assessed at 14 and 28 days. In-vitro experiments with a transwell system were performed to investigate the effects of different stromal cell populations on parietal epithelial cells (PECs) activated or not with albumin or angiotensin II for 24 h. Results Infusions of non-renal and renal stromal cells resulted in a comparable engraftment into the kidney, in the peritubular areas and around the glomerular structures. All three cell populations limited podocyte loss and glomerular endothelial cell injury, and attenuated the formation of podocyte and PEC bridges. This translated into a reduction of glomerulosclerosis and fibrosis. Human ucMSCs had an anti-inflammatory effect superior to that of the other stromal cells, reducing macrophage infiltration and inducing polarisation towards the M2 macrophage phenotype. Conditioned medium from ucMSCs shared the same renoprotective effects of the cells. Consistent with in-vivo data, bmMSCs and kPSCs, but even more so ucMSCs, limited proliferation, migratory potential and extracellular matrix production of activated PECs, when cultured in a transwell system. Conclusions Our data indicate that either non-renal or renal stromal cells induce renal tissue repair, highlighting ucMSCs and their conditioned medium as the most reliable clinical therapeutic tool for CKD patients.
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- 2018
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7. A dual-phase xenon TPC for scintillation and ionisation yield measurements in liquid xenon
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Laura Baudis, Yanina Biondi, Chiara Capelli, Michelle Galloway, Shingo Kazama, Alexander Kish, Payam Pakarha, Francesco Piastra, and Julien Wulf
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Astrophysics ,QB460-466 ,Nuclear and particle physics. Atomic energy. Radioactivity ,QC770-798 - Abstract
Abstract A small-scale, two-phase (liquid/gas) xenon time projection chamber (Xurich II) was designed, constructed and is under operation at the University of Zürich. Its main purpose is to investigate the microphysics of particle interactions in liquid xenon at energies below 50 keV, which are relevant for rare event searches using xenon as target material. Here we describe in detail the detector, its associated infrastructure, and the signal identification algorithm developed for processing and analysing the data. We present the first characterisation of the new instrument with calibration data from an internal $$^{83\mathrm {m}}$$ 83m Kr source. The zero-field light yield is 15.0 and 14.0 photoelectrons/keV at 9.4 and 32.1 keV, respectively, and the corresponding values at an electron drift field of 1 kV/cm are 10.8 and 7.9 photoelectrons/keV. The charge yields at these energies are 28 and 31 electrons/keV, with the proportional scintillation yield of 24 photoelectrons per one electron extracted into the gas phase, and an electron lifetime of 200 $$\upmu $$ μ s. The relative energy resolution, $$\sigma /E$$ σ/E , is 11.9 and 5.8% at 9.4 and 32.1 keV, respectively using a linear combination of the scintillation and ionisation signals. We conclude with measurements of the electron drift velocity at various electric fields, and compare these to literature values.
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- 2018
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8. Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice
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Francesca Sironi, Antonio Vallarola, Martina Bruna Violatto, Laura Talamini, Mattia Freschi, Roberta De Gioia, Chiara Capelli, Azzurra Agostini, Davide Moscatelli, Massimo Tortarolo, Paolo Bigini, Martino Introna, and Caterina Bendotti
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Max 6 ,Amyotrophic lateral sclerosis ,Mesenchymal stem cells ,Umbilical cord ,Transgenic SOD1G93A mice ,Motor neuron ,Gliosis ,Biology (General) ,QH301-705.5 - Abstract
Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression.
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- 2017
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9. Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function
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Luca Perico, Marina Morigi, Cinzia Rota, Matteo Breno, Caterina Mele, Marina Noris, Martino Introna, Chiara Capelli, Lorena Longaretti, Daniela Rottoli, Sara Conti, Daniela Corna, Giuseppe Remuzzi, and Ariela Benigni
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Science - Abstract
Mesenchymal stromal cells drive renal regeneration following injury. Here, the authors show that human mesenchymal stromal cells, when transplanted into mice with acute kidney injury, stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3.
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- 2017
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10. Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice.
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Gianluca Moroncini, Chiara Paolini, Fiorenza Orlando, Chiara Capelli, Antonella Grieco, Cecilia Tonnini, Silvia Agarbati, Eleonora Mondini, Stefania Saccomanno, Gaia Goteri, Silvia Svegliati Baroni, Mauro Provinciali, Martino Introna, Nicoletta Del Papa, and Armando Gabrielli
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Medicine ,Science - Abstract
Lung fibrosis is a severe condition resulting from several interstial lung diseases (ILD) with different etiologies. Current therapy of ILD, especially those associated with connective tissue diseases, is rather limited and new anti-fibrotic strategies are needed. In this study, we investigated the anti-fibrotic activity in vivo of human mesenchymal stromal cells obtained from whole umbilical cord (hUC-MSC). Adult immunocompetent C57BL/6 mice (n. = 8 for each experimental condition) were injected intravenously with hUC-MSC (n. = 2.5 × 105) twice, 24 hours and 7 days after endotracheal injection of bleomycin. Upon sacrifice at days 8, 14, 21, collagen content, inflammatory cytokine profile, and hUC-MSC presence in explanted lung tissue were analyzed. Systemic administration of a double dose of hUC-MSC significantly reduced bleomycin-induced lung injury (inflammation and fibrosis) in mice through a selective inhibition of the IL6-IL10-TGFβ axis involving lung M2 macrophages. Only few hUC-MSC were detected from explanted lungs, suggesting a "hit and run" mechanism of action of this cellular therapy. Our data indicate that hUC-MSC possess strong in vivo anti-fibrotic activity in a mouse model resembling an immunocompetent human subject affected by inflammatory ILD, providing proof of concept for ad-hoc clinical trials.
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- 2018
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11. Longitudinal tracking of triple labeled umbilical cord derived mesenchymal stromal cells in a mouse model of Amyotrophic Lateral Sclerosis
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Martina Bruna Violatto, Chiara Santangelo, Chiara Capelli, Roberta Frapolli, Raffaele Ferrari, Leopoldo Sitia, Massimo Tortarolo, Laura Talamini, Sara Previdi, Davide Moscatelli, Mario Salmona, Martino Introna, Caterina Bendotti, and Paolo Bigini
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Mesenchymal stromal cells ,Umbilical cord ,Amyotrophic Lateral Sclerosis ,Cell tracking ,Nanotechnology ,In vivo imaging ,Biology (General) ,QH301-705.5 - Abstract
The translational potential of cell therapy to humans requires a deep knowledge of the interaction between transplanted cells and host tissues. In this study, we evaluate the behavior of umbilical cord mesenchymal stromal cells (UC-MSCs), labeled with fluorescent nanoparticles, transplanted in healthy or early symptomatic transgenic SOD1G93A mice (a murine model of Amyotrophic Lateral Sclerosis). The double labeling of cells with nanoparticles and Hoechst-33258 enabled their tracking for a long time in both cells and tissues. Whole-body distribution of UC-MSCs was performed by in-vivo and ex-vivo analyses 1, 7, 21 days after single intravenous or intracerebroventricular administration. By intravenous administration cells were sequestered by the lungs and rapidly cleared by the liver. No difference in biodistribution was found among the two groups. On the other hand, UC-MSCs transplanted in lateral ventricles remained on the choroid plexus for the whole duration of the study even if decreasing in number. Few cells were found in the spinal cord of SOD1G93A mice exclusively. No migration in brain parenchyma was observed. These results suggest that the direct implantation in brain ventricles allows a prolonged permanence of cells close to the damaged areas and makes this method of tracking reliable for future studies of efficacy.
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- 2015
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12. Phenotypical and Functional Characteristics of in Vitro-Expanded Adipose-Derived Mesenchymal Stromal Cells from Patients with Systematic Sclerosis
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Chiara Capelli, Eleonora Zaccara, Paola Cipriani, Paola Di Benedetto, Wanda Maglione, Romina Andracco, Gabriele Di Luca, Francesca Pignataro, Roberto Giacomelli, Martino Introna, Claudio Vitali, and Nicoletta Del Papa M.D., U.O.C.
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Medicine - Abstract
Mesenchymal stromal cells (MSCs) have received attention as an ideal source of regenerative cells because of their multipotent differentiation potential. Adipose tissue is an attractive source of MSCs. Recent studies have shown that autologous fat grafting may be effective in the treatment of systemic sclerosis (SSc), but no specific study exists that aimed at investigating whether adipose tissue-derived stromal cells (ADSCs) from SSc patients maintain normal phenotypic and functional characteristics. The purpose of the current study was to investigate whether ADSCs from patients with SSc (SSc-ADSCs) are phenotypically and functionally identical to those from healthy controls (HC-ADSCs). Adipose tissue samples were obtained from 10 patients with SSc and from 8 HCs. Both MSC populations were evaluated for their capacity to (a) express specific MSC surface antigens by flow cytometry analysis, (b) proliferate, (c) differentiate along the adipogenic and osteogenic lineages, (d) suppress in vitro lymphocyte proliferation induced by a mitogenic stimulus, and (e) support endothelial cell (EC) tube formation. ADSCs from SSc patients and HCs showed similar surface phenotype and multilineage differentiation capabilities. In PBMC proliferation inhibition assays, no significant differences were observed between SSc- and HC-ADSCs. Using ADSC/EC cocultures, both SSc- and HC-ADSCs improved tube formation by both HC- and SSc-ECs. This effect was enhanced under hypoxic conditions in all of the cocultures. SSc-ADSCs exhibited the same phenotypic pattern, proliferation and differentiation potentials, and immunosuppressive properties as those from HCs. The proangiogenic activity shown by SSc-ADSCs, namely, under hypoxic conditions, suggests that autologous ADSC grafting may represent a possible therapeutic option for SSc.
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- 2017
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13. Frequent occurrence of non-malignant genetic alterations in clinical grade mesenchymal stromal cells expanded for cell therapy protocols
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Chiara Capelli, Olga Pedrini, Gisella Cassina, Orietta Spinelli, Silvia Salmoiraghi, Josée Golay, Alessandro Rambaldi, Ursula Giussani, and Martino Introna
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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14. Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial
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Antonio Uccelli, Alice Laroni, Rehiana Ali, Mario Alberto Battaglia, Morten Blinkenberg, Lou Brundin, Michel Clanet, Oscar Fernandez, James Marriott, Paolo Muraro, Seyed Massood Nabavi, Roberto S Oliveri, Ernst Radue, Cristina Ramo Tello, Irene Schiavetti, Johann Sellner, Per Soelberg Sorensen, Maria Pia Sormani, Jens Thomas Wuerfel, Mark S Freedman, Naser Aghdami, Eduardo Agüera-Morales, David Allan, Leila Arab, Mario Battaglia, Isabelle Berry, Bruno Bonetti, Chiara Capelli, Lucio Castellan, Maria Cellerino, Maria Teresa Cencioni, Giancarlo Comi, David Courtman, Francesco Dazzi, Anne Fischer-Nielsen, Victoria Fernandez, Mark S. Freedman, Roberto Furlan, Mario Gimona, Francesca Gualandi, Qingdong Guan, Ellen Iacobaeus, Matilde Inglese, Martino Introna, Guillermo Izquierdo, Shahedeh Karimi, Katarina Le Blanc, Sandra Loaiza, Shahrukh Mallik, Stephen Marley, Ruth Ann Marrie, James Marriot, Gianvito Martino, David Miller, Paolo A. Muraro, Richard Nicholas, Giovanni Orengo, Renuka Palanicawande, Matteo Pardini, Ernst W Radue, Carolina Rush, Luc Sensebe, Dirk Strunk, David Szwajcer, and Claire Thalamas
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Adult ,medicine.medical_specialty ,Multiple Sclerosis ,Adolescent ,Placebo ,Young Adult ,Double-Blind Method ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,Cross-Over Studies ,Expanded Disability Status Scale ,business.industry ,Surrogate endpoint ,Multiple sclerosis ,Brain ,Mesenchymal Stem Cells ,Middle Aged ,medicine.disease ,Crossover study ,Malformations of Cortical Development ,Tolerability ,Neurology (clinical) ,business - Abstract
Summary Background Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerability, and activity of autologous MSCs derived from bone marrow and infused intravenously in patients with active multiple sclerosis. Methods MESEMS is a randomised phase 2 trial done at 15 sites in nine countries. Patients (aged 18–50 years) with active relapsing-remitting or progressive multiple sclerosis were included if they had a disease duration of 2–15 years since onset of multiple sclerosis and an Expanded Disability Status Scale score of 2·5–6·5. Patients were randomly assigned (1:1), according to a crossover design, to receive a single intravenous dose of autologous bone marrow-derived MSCs followed by placebo at week 24, or to receive placebo followed by autologous MSCs at week 24, with a follow-up visit at week 48. Primary objectives were to test safety and activity of MSC treatment. The primary safety endpoint was to assess the number and severity of adverse events within each treatment arm. The primary efficacy endpoint was the number of gadolinium-enhancing lesions (GELs) counted over week 4, 12, and 24 compared between treatment groups. The primary efficacy endpoint was assessed in the full analyis set, after all participants completed the week 24 visit. Efficacy endpoints were evaluated using a predefined statistical testing procedure. Safety was monitored throughout the study by recording vital signs and adverse events at each visit. Findings From July 16, 2012, until July 31, 2019, 144 patients were randomly assigned to first receive early intravenous infusion of autologous bone marrow-derived MSCs (n=69) or placebo (n=75). MSC treatment did not meet the primary endpoint of efficacy on the total number of GELs accumulated from baseline to week 24 (rate ratio [RR] 0·94, 95% CI 0·58–1·50; p=0·78). 213 adverse events were recorded, similarly distributed between groups (93 cases recorded in 35 [51%] of 69 patients treated first with MSCs vs 120 cases in 42 [56%] of 75 patients infused first with placebo). The most frequent adverse events reported were infection and infestations, with a total of 54 (25%) of 213 adverse events (18 [19%] of 93 in the early-MSC group and 36 [30%] of 120 in the delayed-MSC group). Nine serious adverse events were reported in seven patients treated with placebo versus none in the MSC group. All serious adverse events were considered to be unrelated to the treatment infusion. No deaths were reported during the study. Interpretation Bone marrow-derived MSC treatment was safe and well tolerated but did not show an effect on GELs, an MRI surrogate marker of acute inflammation, in patients with active forms of multiple sclerosis, at week 24. Thus, this study does not support the use of bone marrow-derived MSCs to treat active multiple sclerosis. Further studies should address the effect of MSCs on parameters related to tissue repair. Funding Fondazione Italiana Sclerosi Multipla (FISM), the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), and the Multiple Sclerosis International Federation (MSIF) for centralised activities. Individual trials participating in the MESEMS network are funded by the following agencies: FISM and Compagnia di San Paolo (Italy); The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors’ Research Foundation (Denmark); the Spanish Health Research Institute Carlos 3 and the Andalusian Public Foundation Progreso y Salud (Spain); the Royan Institute for Stem Cell Biology and Technology (Iran); the Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, and Salzburg (Austria); the Fondation pour l’aide a la recherche sur la sclerose en plaques (ARSEP), French Muscular Dystrophy Association (AFM)-Telethon (France); the UK Multiple Sclerosis Society and the UK Stem Cell Foundation (UK); and the Multiple Sclerosis Society of Canada and The Multiple Sclerosis Scientific Research Foundation and Research Manitoba (Canada).
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- 2021
15. Third-party bone marrow–derived mesenchymal stromal cell infusion before liver transplantation: A randomized controlled trial
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Stefania Camagni, Giuseppe Remuzzi, Caterina Mele, Michele Colledan, M. Zambelli, Matteo Breno, Stefano Fagiuoli, Josée Golay, Marilena Mister, Norberto Perico, Marina Buzzi, Pamela Yossenaidy Rodriguez Ordonez, Chiara Capelli, Manuel Alfredo Podestà, Federica Casiraghi, Matteo Cescon, Lorenzo Maroni, Valentina Rosa Bertuzzo, Alessandro Villa, Marta Todeschini, Antonio Daniele Pinna, Martino Introna, Casiraghi, F, Perico, N, Podesta, M, Todeschini, M, Zambelli, M, Colledan, M, Camagni, S, Fagiuoli, S, Pinna, A, Cescon, M, Bertuzzo, V, Maroni, L, Introna, M, Capelli, C, Golay, J, Buzzi, M, Mister, M, Ordonez, P, Breno, M, Mele, C, Villa, A, Remuzzi, G, Casiraghi, Federica, Perico, Norberto, Podestà, Manuel A, Todeschini, Marta, Zambelli, Marco, Colledan, Michele, Camagni, Stefania, Fagiuoli, Stefano, Pinna, Antonio D, Cescon, Matteo, Bertuzzo, Valentina, Maroni, Lorenzo, Introna, Martino, Capelli, Chiara, Golay, Josee T, Buzzi, Marina, Mister, Marilena, Ordonez, Pamela Y R, Breno, Matteo, Mele, Caterina, Villa, Alessandro, and Remuzzi, Giuseppe, Matteo Ravaioli
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medicine.medical_specialty ,Stromal cell ,medicine.medical_treatment ,Liver transplantation ,clinical research/practice ,Mesenchymal Stem Cell Transplantation ,Gastroenterology ,law.invention ,Randomized controlled trial ,Bone Marrow ,law ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Pharmacology (medical) ,Transplantation ,tolerance ,liver transplantation ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Hepatology ,practice ,stem cell ,Clinical trial ,medicine.anatomical_structure ,clinical research ,hepatology ,Bone marrow ,Stem cell ,business ,liver transplantation/hepatology ,Immunosuppressive Agents - Abstract
Mesenchymal stromal cells (MSC) have emerged as a promising therapy to minimize the immunosuppressive regimen or induce tolerance in solid organ transplantation. In this randomized open-label phase Ib/IIa clinical trial, 20 liver transplant patients were randomly allocated (1:1) to receive a single pre-transplant intravenous infusion of third-party bone marrow-derived MSC or standard of care alone. The primary end-point was the safety profile of MSC administration during the one-year follow-up. Nineteen patients completed the study, and none of those who received MSC experienced infusion-related complications. The incidence of serious and non-serious adverse events was similar in the two groups. Circulating Treg/memory Treg and tolerant NK subset of CD56bright NK cells increased slightly over baseline, albeit not to a statistically significant extent, in MSC-treated patients but not in the control group. Graft function and survival, as well as histologic parameters and intragraft expression of tolerance-associated transcripts in 1-year protocol biopsies were similar in the two groups. In conclusion, pre-transplant MSC infusion in liver transplant recipients was safe and induced mild positive changes in immunoregulatory T and NK cells in the peripheral blood. This study opens the way for a trial on possible tolerogenic efficacy of MSC in liver transplantation. ClinicalTrials.gov identifier: NCT02260375.
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- 2021
16. Double-weak decays of Xe124 and Xe136 in the XENON1T and XENONnT experiments
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Manfred Lindner, Miguel Silva, Juehang Qin, Chiara Capelli, Teresa Marrodán Undagoitia, Jose Javier Cuenca Garcia, Andrea Gallo Rosso, Luca Grandi, Isaac Sarnoff, Michelle Galloway, Kaixuan Ni, Walter Fulgione, Francesco Toschi, Alexander Bismark, Joseph Howlett, Emanuele Angelino, JOSÉ MATIAS-LOPES, Lorenzo Bellagamba, Adam Brown, Florian Jörg, Marc Schumann, and Joaquim Palacio Navarro
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- 2022
17. Immune Reconstitution Following Infusion of Autologous Blinatumomab Expanded T-Cells (BET) in CD20+ Indolent Non-Hodgkin Lymphomas and Chronic Lymphocytic Leukemia Receiving Front-Line Treatment with Fludarabine-Cyclophosphamide-Rituximab or Bendamustine-Rituximab
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Giuseppe Gritti, Federico Lussana, Silvia Ferrari, Anna Maria Barbui, Francesco Landi, Giulia Quaresmini, Gianmaria Borleri, Muriel Paganessi, Chiara Pavoni, Elisa Gotti, Chiara Capelli, Josee Golay, Martino Introna, and Alessandro Rambaldi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
18. Final Results of Phase I/II Study of Donor-Derived CAR T Cells Engineered with Sleeping Beauty in Pediatric and Adult Patients with B-Cell Acute Lymphoblastic Leukemia Relapsed Post-HSCT
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Federico Lussana, Chiara Francesca Magnani, Giuseppe Gaipa, Stefania Galimberti, Giuseppe Gritti, Daniela Belotti, Sara Napolitano, Chiara Buracchi, Gian Maria Borleri, Benedetta Rambaldi, Giuliana Rizzuto, Anna Grassi, Muriel Paganessi, Silvia Ferrari, Sarah Tettamanti, Giovanni Gazzaniga, Chiara Capelli, Elisa Gotti, Martino Introna, Adriana Balduzzi, Maria Grazia Valsecchi, Giuseppe Dastoli, Alessandro Rambaldi, and Andrea Biondi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
19. Carcik-CD19 Cells Expand In Vivo Toward a CD8+ Memory Phenotype and Their Persistence Is Associated with a Longer Duration of Response
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Benedetta Rambaldi, Stefania Galimberti, Giuliana Rizzuto, Chiara Francesca Magnani, Chiara Buracchi, Giulia Risca, Martina Paredi, Daniela Belotti, Alex Moretti, Marianna Ponzo, Sarah Tettamanti, Gian Maria Borleri, Cristian Meli, Muriel Paganessi, Silvia Zaninelli, Elisa Gotti, Chiara Capelli, Martino Introna, Federico Lussana, Giuseppe Gritti, Silvia Ferrari, Anna Grassi, Sara Napolitano, Adriana Balduzzi, Maria Grazia Valsecchi, Giuseppe Dastoli, Alessandro Rambaldi, Andrea Biondi, and Giuseppe Gaipa
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
20. Search for neutrinoless β+ EC decay of Te120 with CUORE
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Cristian Pira, Chiara Capelli, Stefano Ghislandi, Alessio Caminata, Stefano Di Lorenzo, Francesca Del Corso, Massimiliano Clemenza, ALBERTO RESSA, Fabio Bellini, Brian Fujikawa, Simone Quitadamo, Roger Huang, Lindley Winslow, Karsten Heeger, and Giovanni Benato
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- 2022
21. A comprehensive report of long-term stability data for a range ATMPs: A need to develop guidelines for safe and harmonized stability studies
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Chiara Capelli, Simona Frigerio, Daniela Lisini, Sara Nava, Giuseppe Gaipa, Daniela Belotti, Benedetta Cabiati, Silvia Budelli, Lorenza Lazzari, Jessica Bagnarino, Matteo Tanzi, Patrizia Comoli, Norberto Perico, Martino Introna, Josée Golay, Capelli, C, Frigerio, S, Lisini, D, Nava, S, Gaipa, G, Belotti, D, Cabiati, B, Budelli, S, Lazzari, L, Bagnarino, J, Tanzi, M, Comoli, P, Perico, N, Introna, M, and Golay, J
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Cryopreservation ,Cancer Research ,Transplantation ,Cell Survival ,Immunology ,Cell Differentiation ,Cell Biology ,stability study ,potency assay ,Immunophenotyping ,Good Manufacturing Practice ,Oncology ,Immunology and Allergy ,shelf life ,advanced therapy medicinal product ,quality control ,Genetics (clinical) - Abstract
Background aims: Advanced therapy medicinal products (ATMPs) are novel drugs based on genes, cells or tissues developed to treat many different diseases. Stability studies of each new ATMP need to be performed to define its shelf life and guarantee efficacy and safety upon infusion, and these are presently based on guidelines originally drafted for standard pharmaceutical drugs, which have properties and are stored in conditions quite different from cell products. The aim of this report is to provide evidence-based information for stability studies on ATMPs that will facilitate the interlaboratory harmonization of practices in this area. Methods: We have collected and analyzed the results of stability studies on 19 different cell-based experimental ATMPs, produced by five authorized cell factories forming the Lombardy “Plagencell network” for use in 36 approved phase I/II clinical trials; most were cryopreserved and stored in liquid nitrogen vapors for 1 to 13 years. Results: The cell attributes collected in stability studies included cell viability, immunophenotype and potency assays, in particular immunosuppression, cytotoxicity, cytokine release and proliferation/differentiation capacity. Microbiological attributes including sterility, endotoxin levels and mycoplasma contamination were also analyzed. All drug products (DPs), cryopreserved in various excipients containing 10% DMSO and in different primary containers, were very stable long term at
- Published
- 2021
22. Protective Effects of Human Nonrenal and Renal Stromal Cells and Their Conditioned Media in a Rat Model of Chronic Kidney Disease
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Marina Morigi, Claudia Elisa Carminati, Chiara Capelli, Cinzia Rota, Ariela Benigni, Carlamaria Zoja, Daniëlle G. Leuning, Domenico Cerullo, Martino Introna, Ton J. Rabelink, Giuseppe Remuzzi, Barbara Imberti, Valerie A. Luyckx, Monica Locatelli, Daniela Corna, and Anna Pezzotta
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0301 basic medicine ,medicine.medical_specialty ,Stromal cell ,030232 urology & nephrology ,Biomedical Engineering ,renal repair ,lcsh:Medicine ,Podocyte ,Cell therapy ,Nephrin ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Internal medicine ,medicine ,Animals ,Humans ,Renal Insufficiency, Chronic ,stromal cells ,Transplantation ,biology ,business.industry ,Mesenchymal stem cell ,lcsh:R ,Cell Biology ,medicine.disease ,Rats ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,conditioned medium ,biology.protein ,renal perivascular cells ,Original Article ,business ,Myofibroblast ,chronic kidney disease ,Kidney disease - Abstract
Mesenchymal stromal cells (MSCs) are emerging as a novel therapeutic option for limiting chronic kidney disease progression. Conditioned medium (CM) containing bioactive compounds could convey similar benefits, avoiding the potential risks of cell therapy. This study compared the efficacy of nonrenal and renal cell-based therapy with the corresponding CM in rats with renal mass reduction (RMR). Infusions of human kidney stromal cells (kPSCs) and CM-kPSCs, but not umbilical cord (uc) MSCs or CM-ucMSCs, reduced proteinuria and preserved podocyte number and nephrin expression in RMR rats. Glomerular fibrosis, microvascular rarefaction, and apoptosis were reduced by all treatments, while the peritubular microvascular loss was reduced by kPSCs and CM-kPSCs treatment only. Importantly, kPSCs and CM-kPSCs reduced NG2-positive pericytes, and all therapies reduced α-smooth muscle actin expression, indicating reduced myofibroblast expansion. Treatment with kPSCs also significantly inhibited the accumulation of ED1-positive macrophages in the renal interstitium of RMR rats. These findings demonstrate that the CM of ucMSCs and kPSCs confers similar renoprotection as the cells. kPSCs and CM-kPSCs may be superior in attenuating chronic renal injury as a cell source.
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- 2020
23. Utility of routine evaluation of sterility of cellular therapy products with or without extensive manipulation: Best practices and clinical significance
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Mara Magri, Chiara Capelli, Marco Passera, Elisa Gotti, Josée Golay, Francesca Vailati, Gianmaria Borleri, Martino Introna, Alessandro Rambaldi, Claudio Farina, and Olga Pedrini
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Cancer Research ,medicine.medical_specialty ,Time Factors ,Sterility ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,Antibiotics ,Cell- and Tissue-Based Therapy ,Context (language use) ,Hematopoietic stem cell transplantation ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Good manufacturing practice ,Genetics (clinical) ,Transplantation ,business.industry ,Mesenchymal stem cell ,Hematopoietic Stem Cell Transplantation ,Sterilization ,Mesenchymal Stem Cells ,Cell Biology ,Hematopoietic Stem Cells ,Culture Media ,medicine.anatomical_structure ,Oncology ,chemistry ,Blood Component Removal ,Bone marrow ,ATMP ,business ,030215 immunology - Abstract
Background We analyzed the results of routine sterility testing performed in our center over the last 10 years, in the context both hematopoietic stem cell transplantation (HSCT) and Advanced Therapeutic Medicinal Products (ATMPs). Methods For sterility tests 14-day cultures were performed in culture media detecting aerobic and anaerobic microorganisms. Results In this study, 22/1643 (1.3%) of apheretic products for autologous or allogeneic HSCT were contaminated, whereas 14/73 bone marrow (BM) harvests (17.8%) were positive. In 22 cases, the contaminated HSCs were infused to patients, but there was no evidence of any adverse impact of contamination on the hematologic engraftment or on infections. Indeed none of the five positive hemocultures detected in patients following infusion could be linked to the contaminated stem cell product. Our Cell Factory also generated 286 ATMPs in good manufacturing practice (GMP) conditions since 2007 and all final products were sterile. In three cases of mesenchymal stromal cell expansions, the starting BM harvests were contaminated, but the cell products at the end of expansion were sterile, presumably thanks to the presence of an antibiotic in the culture medium. Discussion The decreased rate of contamination of cell harvests observed with time suggests that routine sterility testing and communication of the results to the collecting centers may improve clinical practices. Furthermore, we recommend the use of antibiotics in the medium for ATMP expansion, to decrease the likelihood of expanding microorganisms within clean rooms. Finally we discuss the costs of sterility testing of ATMPs by GMP-approved external laboratories.
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- 2018
24. Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function
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Lorena Longaretti, Giuseppe Remuzzi, Caterina Mele, Marina Morigi, Chiara Capelli, Ariela Benigni, Martino Introna, Matteo Breno, Cinzia Rota, Daniela Rottoli, Marina Noris, Daniela Corna, Sara Conti, and Luca Perico
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0301 basic medicine ,SIRT3 ,Science ,General Physics and Astronomy ,Mice, SCID ,Mesenchymal Stem Cell Transplantation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Adenosine Triphosphate ,0302 clinical medicine ,Sirtuin 3 ,medicine ,Animals ,Humans ,lcsh:Science ,Cell Proliferation ,Multidisciplinary ,biology ,Cell growth ,Regeneration (biology) ,Mesenchymal stem cell ,Acute kidney injury ,Mesenchymal Stem Cells ,General Chemistry ,Acute Kidney Injury ,NAD ,medicine.disease ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Mitochondria ,Cell biology ,Kidney Tubules ,030104 developmental biology ,Mitochondrial biogenesis ,030220 oncology & carcinogenesis ,Immunology ,Sirtuin ,biology.protein ,Female ,lcsh:Q ,NAD+ kinase ,Cisplatin - Abstract
Mesenchymal stromal cells (MSCs) are renoprotective and drive regeneration following injury, although cellular targets of such an effect are still ill-defined. Here, we show that human umbilical cord (UC)-MSCs transplanted into mice stimulate tubular cells to regain mitochondrial mass and function, associated with enhanced microtubule-rich projections that appear to mediate mitochondrial trafficking to create a reparative dialogue among adjacent tubular cells. Treatment with UC-MSCs in mice with cisplatin-induced acute kidney injury (AKI) regulates mitochondrial biogenesis in proximal tubuli by enhancing PGC1α expression, NAD+ biosynthesis and Sirtuin 3 (SIRT3) activity, thus fostering antioxidant defenses and ATP production. The functional role of SIRT3 in tubular recovery is highlighted by data that in SIRT3-deficient mice with AKI, UC-MSC treatment fails to induce renoprotection. These data document a previously unrecognized mechanism through which UC-MSCs facilitate renal repair, so as to induce global metabolic reprogramming of damaged tubular cells to sustain energy supply., Mesenchymal stromal cells drive renal regeneration following injury. Here, the authors show that human mesenchymal stromal cells, when transplanted into mice with acute kidney injury, stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3.
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- 2017
25. Induction of Mouse Lung Injury by Endotracheal Injection of Bleomycin
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Mauro Provinciali, Silvia Agarbati, Armando Gabrielli, Martino Introna, A. Grieco, Chiara Paolini, Chiara Capelli, Fiorenza Orlando, Gianluca Moroncini, and C. Tonnini
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Pathology ,medicine.medical_specialty ,General Chemical Engineering ,Pulmonary Fibrosis ,Lung injury ,Bleomycin ,Mesenchymal Stem Cell Transplantation ,General Biochemistry, Genetics and Molecular Biology ,Umbilical Cord ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Fibrosis ,In vivo ,Pulmonary fibrosis ,Medicine ,Animals ,0303 health sciences ,General Immunology and Microbiology ,business.industry ,General Neuroscience ,030305 genetics & heredity ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Lung Injury ,respiratory system ,medicine.disease ,Pathophysiology ,respiratory tract diseases ,Mice, Inbred C57BL ,Trachea ,Disease Models, Animal ,chemistry ,Systemic administration ,Female ,business - Abstract
Pulmonary fibrosis is a hallmark of several human lung diseases with a different etiology. Since current therapies are rather limited, mouse models continue to be an essential tool for developing new antifibrotic strategies. Here we provide an effective method to investigate in vivo antifibrotic activity of human mesenchymal stromal cells obtained from whole umbilical cord (hUC-MSC) in attenuating bleomycin-induced lung injury. C57BL/6 mice receive a single endotracheal injection of bleomycin (1.5 U/kg body weight) followed by a double infusion of hUC-MSC (2.5 x 105) into the tail vein, 24 h and 7 days after the bleomycin administration. Upon sacrifice at days 8, 14, or 21, inflammatory and fibrotic changes, collagen content, and hUC-MSC presence in explanted lung tissue are analyzed. The injection of bleomycin into the mouse trachea allows the direct targeting of the lungs, leading to extensive pulmonary inflammation and fibrosis. The systemic administration of a double dose of hUC-MSC results in the early blunting of the bleomycin-induced lung injury. Intravenously infused hUC-MSC are transiently engrafted into the mouse lungs, where they exert their anti-inflammatory and antifibrotic activity. In conclusion, this protocol has been successfully applied for the preclinical testing of hUC-MSC in an experimental mouse model of human pulmonary fibrosis. However, this technique can be easily extended both to study the effect of different endotracheally administered substances on the pathophysiology of the lungs and to validate new anti-inflammatory and antifibrotic systemic therapies.
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- 2019
26. Therapeutic potential of stromal cells of non-renal or renal origin in experimental chronic kidney disease
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Martino Introna, Ariela Benigni, Domenico Cerullo, Ornella Colpani, Daniela Rottoli, Giuseppe Remuzzi, Carlamaria Zoja, Daniela Corna, Ton J. Rabelink, Daniëlle G. Leuning, Marina Morigi, Chiara Capelli, and Cinzia Rota
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0301 basic medicine ,Male ,Medicine (miscellaneous) ,Mesenchymal stromal cell therapy ,Podocyte ,Umbilical Cord ,0302 clinical medicine ,Chronic kidney disease ,lcsh:QD415-436 ,Kidney ,lcsh:R5-920 ,Renal perivascular cells ,Glomerulosclerosis, Focal Segmental ,Podocytes ,Graft Survival ,Antigens, Nuclear ,medicine.anatomical_structure ,Molecular Medicine ,Stem cell ,lcsh:Medicine (General) ,Stromal cell ,Transplantation, Heterologous ,Bone Marrow Cells ,Mesenchymal Stem Cell Transplantation ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Nephropathy ,lcsh:Biochemistry ,03 medical and health sciences ,Rats, Nude ,Renal repair ,medicine ,Animals ,Humans ,Regeneration ,Renal Insufficiency, Chronic ,Conditioned medium ,Cell Proliferation ,business.industry ,Macrophages ,Research ,Mesenchymal stem cell ,Epithelial Cells ,Mesenchymal Stem Cells ,Cell Biology ,medicine.disease ,Coculture Techniques ,Rats ,Disease Models, Animal ,030104 developmental biology ,Doxorubicin ,Culture Media, Conditioned ,Cancer research ,Bone marrow ,business ,030217 neurology & neurosurgery ,Biomarkers ,Kidney disease - Abstract
Background Mesenchymal stromal cell (MSC)-based therapy is a promising strategy for preventing the progression of chronic kidney disease (CKD), with the potential to induce tissue regeneration. In search of the best cellular source we compared, in the rat model of adriamycin (ADR) nephropathy, the regenerative potential of human stromal cells of non-renal origin, such as bone marrow (bm) MSCs and umbilical cord (uc) MSCs, with that of newly discovered stromal cells of renal origin, the kidney perivascular cells (kPSCs) known to exhibit tissue-specific properties. Methods The therapeutic effect of repeated infusions of human bmMSCs, ucMSCs, kPSCs (1.5 × 106 cells/rats) or conditioned medium from ucMSCs was studied in athymic rats with ADR-induced nephropathy (7.9 mg/kg). The ability of the three stromal cell populations to engraft the damaged kidney was evaluated by detecting the presence of human nuclear antigenpos cells. Glomerular podocyte loss and endothelial damage, sclerotic lesions and inflammation were assessed at 14 and 28 days. In-vitro experiments with a transwell system were performed to investigate the effects of different stromal cell populations on parietal epithelial cells (PECs) activated or not with albumin or angiotensin II for 24 h. Results Infusions of non-renal and renal stromal cells resulted in a comparable engraftment into the kidney, in the peritubular areas and around the glomerular structures. All three cell populations limited podocyte loss and glomerular endothelial cell injury, and attenuated the formation of podocyte and PEC bridges. This translated into a reduction of glomerulosclerosis and fibrosis. Human ucMSCs had an anti-inflammatory effect superior to that of the other stromal cells, reducing macrophage infiltration and inducing polarisation towards the M2 macrophage phenotype. Conditioned medium from ucMSCs shared the same renoprotective effects of the cells. Consistent with in-vivo data, bmMSCs and kPSCs, but even more so ucMSCs, limited proliferation, migratory potential and extracellular matrix production of activated PECs, when cultured in a transwell system. Conclusions Our data indicate that either non-renal or renal stromal cells induce renal tissue repair, highlighting ucMSCs and their conditioned medium as the most reliable clinical therapeutic tool for CKD patients. Electronic supplementary material The online version of this article (10.1186/s13287-018-0960-8) contains supplementary material, which is available to authorized users.
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- 2018
27. Longitudinal tracking of triple labeled umbilical cord derived mesenchymal stromal cells in a mouse model of Amyotrophic Lateral Sclerosis
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Massimo Tortarolo, Laura Talamini, Davide Moscatelli, Chiara Santangelo, Roberta Frapolli, Sara Previdi, Raffaele Ferrari, Chiara Capelli, Martino Introna, Paolo Bigini, Caterina Bendotti, Leopoldo Sitia, Mario Salmona, and Martina Bruna Violatto
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Biodistribution ,Pathology ,medicine.medical_specialty ,Mesenchymal stromal cells ,Mice, Transgenic ,Biology ,Mesenchymal Stem Cell Transplantation ,Umbilical cord ,Cell therapy ,Lateral ventricles ,Parenchyma ,medicine ,Amyotrophic Lateral Sclerosis ,Cell tracking ,In vivo imaging ,Nanotechnology ,Cell Biology ,Developmental Biology ,Medicine (all) ,Animals ,Humans ,Tissue Distribution ,lcsh:QH301-705.5 ,Cell Size ,Injections, Intraventricular ,Medicine(all) ,Staining and Labeling ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,General Medicine ,Anatomy ,Spinal cord ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,lcsh:Biology (General) ,Organ Specificity ,Injections, Intravenous ,Choroid plexus - Abstract
The translational potential of cell therapy to humans requires a deep knowledge of the interaction between transplanted cells and host tissues. In this study, we evaluate the behavior of umbilical cord mesenchymal stromal cells (UC-MSCs), labeled with fluorescent nanoparticles, transplanted in healthy or early symptomatic transgenic SOD1G93A mice (a murine model of Amyotrophic Lateral Sclerosis). The double labeling of cells with nanoparticles and Hoechst-33258 enabled their tracking for a long time in both cells and tissues. Whole-body distribution of UC-MSCs was performed by in-vivo and ex-vivo analyses 1, 7, 21days after single intravenous or intracerebroventricular administration. By intravenous administration cells were sequestered by the lungs and rapidly cleared by the liver. No difference in biodistribution was found among the two groups. On the other hand, UC-MSCs transplanted in lateral ventricles remained on the choroid plexus for the whole duration of the study even if decreasing in number. Few cells were found in the spinal cord of SOD1G93A mice exclusively. No migration in brain parenchyma was observed. These results suggest that the direct implantation in brain ventricles allows a prolonged permanence of cells close to the damaged areas and makes this method of tracking reliable for future studies of efficacy.
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- 2015
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28. Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice
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Paolo Bigini, Caterina Bendotti, Martino Introna, Chiara Capelli, Azzurra Agostini, Mattia Freschi, Roberta De Gioia, Davide Moscatelli, Laura Talamini, Francesca Sironi, Antonio Vallarola, Martina Bruna Violatto, and Massimo Tortarolo
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0301 basic medicine ,Male ,Pathology ,Motor neuron ,medicine.medical_treatment ,Inbred C57BL ,Umbilical cord ,Transgenic ,Umbilical Cord ,Mice ,Superoxide Dismutase-1 ,Gliosis ,Amyotrophic lateral sclerosis ,Max 6 ,Mesenchymal stem cells ,Transgenic SOD1G93A mice ,lcsh:QH301-705.5 ,Motor Neurons ,Mesenchymal Stromal Cells ,General Medicine ,Anatomy ,Stem-cell therapy ,3. Good health ,medicine.anatomical_structure ,Female ,medicine.symptom ,medicine.medical_specialty ,Mice, Transgenic ,Biology ,Amyotrophic Lateral Sclerosis ,Animals ,Humans ,Mice, Inbred C57BL ,Point Mutation ,Mesenchymal Stem Cell Transplantation ,Developmental Biology ,Cell Biology ,Neuroprotection ,03 medical and health sciences ,medicine ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Spinal cord ,Lumbar Spinal Cord ,030104 developmental biology ,lcsh:Biology (General) - Abstract
Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression.
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- 2017
29. Phenotypical and functional characteristics of in vitro-expanded adipose-derived mesenchymal stromal cells from patients with systematic sclerosis
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Paola Di Benedetto, R. Andracco, Claudio Vitali, Gabriele Di Luca, Roberto Giacomelli, Francesca Pignataro, Martino Introna, Wanda Maglione, Eleonora Zaccara, Nicoletta Del Papa, Chiara Capelli, and Paola Cipriani
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0301 basic medicine ,Stromal cell ,Mesenchymal stromal cells (MSCs) ,Adipose tissue ,Systemic sclerosis (SSc) ,Adipose Tissue ,Cell Differentiation ,Cell Hypoxia ,Cell Proliferation ,Cells, Cultured ,Coculture Techniques ,Humans ,Immunophenotyping ,Leukocytes, Mononuclear ,Mesenchymal Stem Cells ,Sclerosis ,Cells ,Mononuclear ,Biomedical Engineering ,lcsh:Medicine ,Lymphocyte proliferation ,Biology ,Article ,Flow cytometry ,03 medical and health sciences ,medicine ,Leukocytes ,skin and connective tissue diseases ,Tube formation ,Transplantation ,Cultured ,medicine.diagnostic_test ,integumentary system ,Mesenchymal stem cell ,lcsh:R ,Cell Biology ,Endothelial stem cell ,030104 developmental biology ,Adipogenesis ,Cancer research - Abstract
Mesenchymal stromal cells (MSCs) have received attention as an ideal source of regenerative cells because of their multipotent differentiation potential. Adipose tissue is an attractive source of MSCs. Recent studies have shown that autologous fat grafting may be effective in the treatment of systemic sclerosis (SSc), but no specific study exists that aimed at investigating whether adipose tissue-derived stromal cells (ADSCs) from SSc patients maintain normal phenotypic and functional characteristics. The purpose of the current study was to investigate whether ADSCs from patients with SSc (SSc-ADSCs) are phenotypically and functionally identical to those from healthy controls (HC-ADSCs). Adipose tissue samples were obtained from 10 patients with SSc and from 8 HCs. Both MSC populations were evaluated for their capacity to (a) express specific MSC surface antigens by flow cytometry analysis, (b) proliferate, (c) differentiate along the adipogenic and osteogenic lineages, (d) suppress in vitro lymphocyte proliferation induced by a mitogenic stimulus, and (e) support endothelial cell (EC) tube formation. ADSCs from SSc patients and HCs showed similar surface phenotype and multilineage differentiation capabilities. In PBMC proliferation inhibition assays, no significant differences were observed between SSc- and HC-ADSCs. Using ADSC/EC cocultures, both SSc- and HC-ADSCs improved tube formation by both HC- and SSc-ECs. This effect was enhanced under hypoxic conditions in all of the cocultures. SSc-ADSCs exhibited the same phenotypic pattern, proliferation and differentiation potentials, and immunosuppressive properties as those from HCs. The proangiogenic activity shown by SSc-ADSCs, namely, under hypoxic conditions, suggests that autologous ADSC grafting may represent a possible therapeutic option for SSc.
- Published
- 2017
30. Treatment of Graft versus Host Disease with Mesenchymal Stromal Cells: A Phase I Study on 40 Adult and Pediatric Patients
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Francesca Masciocchi, Attilio Rovelli, Giovanna D'Amico, Sergio Cortelazzo, Adriana Balduzzi, Anna Grassi, Ettore Biagi, Martino Introna, Olga Pedrini, Giovanna Lucchini, Paolo Perseghin, Andrea Biondi, Giuseppe Gaipa, Daniela Longoni, Chiara Capelli, Stefania Galimberti, Erica Dander, Enrico Maria Pogliani, Fabio Pavan, Irene Cavattoni, Matteo Parma, Sara Deola, Josée Golay, Alessandra Algarotti, Daniela Belotti, Caterina Micò, Alessandro Rambaldi, Introna, M, Lucchini, G, Dander, E, Galimberti, S, Rovelli, A, Balduzzi, A, Longoni, D, Pavan, F, Masciocchi, F, Algarotti, A, Micò, C, Grassi, A, Deola, S, Cavattoni, I, Gaipa, G, Belotti, D, Perseghin, P, Parma, M, Pogliani, E, Golay, J, Pedrini, O, Capelli, C, Cortelazzo, S, D'Amico, G, Biondi, A, Rambaldi, A, and Biagi, E
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Mesenchymal stromal cells ,Graft vs Host Disease ,Antineoplastic Agents ,Disease ,Mesenchymal Stem Cell Transplantation ,Severity of Illness Index ,Gastroenterology ,Steroid refractory graft-versus-host disease (GVHD) ,Cell therapy ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Child ,Adverse effect ,Aged ,Transplantation ,Mesenchymal stromal cell ,business.industry ,Remission Induction ,Mesenchymal stem cell ,Infant ,Immunosuppression ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Acute toxicity ,Immunosuppressive treatment ,Surgery ,Graft-versus-host disease ,Drug Resistance, Neoplasm ,Child, Preschool ,Hematologic Neoplasms ,Hematopoietic stem cell transplantation (HSCT) ,Female ,Steroids ,Platelet lysate ,business ,Immunosuppressive Agents - Abstract
This phase I multicenter study was aimed at assessing the feasibility and safety of intravenous administration of third party bone marrow–derived mesenchymal stromal cells (MSC) expanded in platelet lysate in 40 patients (15 children and 25 adults), experiencing steroid-resistant grade II to IV graft-versus-host disease (GVHD). Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 × 106/kg per infusion was administered. No acute toxicity was reported. Overall, 86 adverse events and serious adverse events were reported in the study, most of which (72.1%) were of infectious nature. Overall response rate, measured at 28 days after the last MSC injection, was 67.5%, with 27.5% complete response. The latter was significantly more frequent in patients exhibiting grade II GVHD as compared with higher grades (61.5% versus 11.1%, P = .002) and was borderline significant in children as compared with adults (46.7 versus 16.0%, P = .065). Overall survival at 1 and 2 years from the first MSC administration was 50.0% and 38.6%, with a median survival time of 1.1 years. In conclusion, MSC can be safely administered on top of conventional immunosuppression for steroid resistant GVHD treatment. Eudract Number 2008-007869-23, NCT01764100.
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- 2014
31. Molecular events underlying interleukin-6 independence in a subclone of the CMA-03 multiple myeloma cell line
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Antonino Neri, Donata Verdelli, Martino Introna, Chiara Capelli, Roberto Piva, Luca Baldini, Elisa Pellegrino, Raffaella Chiaramonte, Marianna D'Anca, Sonia Fabris, Laura Mosca, Giorgio Inghirami, Lucia Nobili, Katia Todoerti, and Luigia Lombardi
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Cancer Research ,biology ,Bortezomib ,humanities ,Gene expression profiling ,Cell culture ,Immunology ,Genetics ,biology.protein ,Cancer research ,medicine ,Viability assay ,Signal transduction ,STAT3 ,Autocrine signalling ,health care economics and organizations ,STAT5 ,medicine.drug - Abstract
We explored the molecular mechanisms involved in the establishement of CMA-03/06, an IL-6-independent variant of the multiple myeloma cell line CMA-03 previously generated in our Institution. CMA-03/06 cells grow in the absence of IL-6 with a doubling time comparable with that of CMA-03 cells; neither the addition of IL6 (IL-6) to the culture medium nor co-culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL-6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL-6 independence of CMA-03/06 cells is not apparently due to the development of an autocrine IL-6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA-03/06 cells showed an activated pattern of the NF-κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA-03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA-03/06 cells display a higher sensibility to NF-κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL-6 independence of CMA-03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell-line CMA-03 and its variant CMA-03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL-6-independent growth of myeloma cells.
- Published
- 2013
32. Human Umbilical Cord Derived Mesenchymal Stromal Cells to Treat Steroid-Refractory Acute GvHD III/IV or Overlap Syndrome: Interim Analysis of a Multicenter Phase I/II Study
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Daniela Taurino, Alessandra Algarotti, Maria Chiara Finazzi, Martino Introna, Chiara Capelli, Maria Luisa Ferrari, Chiara Pavoni, Maria Caterina Mico, Anna De Grassi, Francesco Onida, Nicola Mordini, Alessandro Rambaldi, and Federico Lussana
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Mesenchymal stem cell ,Overlap syndrome ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Interim analysis ,Biochemistry ,Umbilical cord ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Graft-versus-host disease ,medicine ,Pentostatin ,business ,medicine.drug - Abstract
Background Treatment of patients developing steroid-refractory acute GvHD (SR-aGvHD) after allogeneic hematopoietic cell transplantation (HCT) remains an unmet clinical need and a major therapeutic challenge. Mesenchymal stromal cells (MSC) induce immunosuppression and reduce the inflammatory status initiated by aGvHD. We performed an interim analysis of a multicenter, prospective, non-randomized, phase I/II study, planned to test the safety and activity of human umbilical cord (UC), third-party MSC given sequentially after Pentatostatin for the treatment of SR-aGvHD grade III-IV as well as the overlap syndrome (EUDRACT n. 2012-000582-21), NCT02032446). Patients and Methods Third-party UC MSC were produced under GMP conditions as previously described (Capelli C et al Cytotherapy, 2011, 13, 786-801). The treatment schedule was based on the sequential administration of Pentostatin, given iv at dose of 1 mg/m^2 for 3 consecutive days, followed by 3 MSC infusions given at weekly intervals. Between October 2013 and May 2018 (range 4.6 years) we enrolled 27 allogeneic HCT adult recipients (22 male) with SR-aGvHD (n 25) or overlap syndrome (n 2), median age 47 years (range 19-62) transplanted from HLA-identical sibling donors (6; 22%), haploidentical donors (2; 7%), unrelated donors (18; 67%) or cord blood (1; 4%). Target organ involvement included skin in 11 cases (44%), gastrointestinal tract (GI) in 23 (92%) and liver in 12 (48%). Nine patients had grade III (33%), 16 patients grade IV (60%) and 2 patients had severe overlap syndrome (7%). Most of patients exhibited multiple organ involvement (n 16, 64%). Patients started MSC therapy at median of 22 days (10-2101) after the onset of aGvHD or overlap syndrome. Results The infusions of UC MSC-infusion were always well tolerated without any immediate or late toxic event. Response to MSC therapy, by day 30 after the final MSC dose, was evaluable in 16 of 27 patients: 7 achieved CR (26%), 6 PR (22%) and 3 NR (11%). Ten patients died before reaching the evaluation time of response: 8 patients for aGvHD and 2 for haematological disease. One patient was lost to follow up after 9 days from the last UC-MSC infusion. Remarkably, the subgroup of patients with single organ involvement (8 GI, 1 liver) were all evaluable showing 6 patients in overall response (67%, 4 RC and 2 PR). No response was observed in 2 cases of severe overlap syndrome. Patients achieving CR had improved longer term OS vs patients in PR/NR (80% vs 50% at 1 year). For patients with grade III and IV SR-aGvHD, CR rates at day 30 were 67% and 31% respectively. During tapering of steroid therapy 4 out of 7 patients that obtained CR had aGvHD recurrence, at median time of 87 days. We observed relapse of underlying malignancy in 5 patients and all died with active disease. At last follow-up 8 out of 27 patients were alive with no GVHD in 5 of them; 14 patients died from TRM: aGvHD or overlap syndrome itself (n=10), infections (n= 2), cGvHD (n= 2). Two patients with uncontrolled GvHD had clinical signs of Transplant Associated Microangiopathy (TAM). A total of 17 reported AE and 12 SAE were registered. In 23 out of 27 patients infectious complications were observed, in most cases virus related (n.25; CMV followed by BK virus and EBV), and fungal infections (3 aspergillus pneumoniae). Blood-stream documented infections (5) and pneumoniae (5) were also observed. Conclusions The infusion of cord blood derived MSC proved safe in all cases. As expected in patients with steroid refractory aGvHD, a high rate of infectious complications were observed. When considering that most patients (60 %) had grade IV aGvHD, the response rate and the OS are promising and this warrants not only the completion of this Phase I/II study but also planning a future pivotal trial. Disclosures No relevant conflicts of interest to declare.
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- 2018
33. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation
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Martino Introna, Federica Casiraghi, Marina Noris, Norberto Perico, Giuseppe Remuzzi, Regiane Aparecida Cavinato, Marta Todeschini, Paola Cassis, Eliana Gotti, Paola Rizzo, Monica Cortinovis, Chiara Capelli, and Alessandro Rambaldi
- Subjects
Adult ,Graft Rejection ,Male ,medicine.medical_specialty ,Basiliximab ,Recombinant Fusion Proteins ,Population ,Urology ,Mesenchymal Stem Cell Transplantation ,T-Lymphocytes, Regulatory ,Clinical Protocols ,Transplantation Immunology ,medicine ,Humans ,education ,Kidney transplantation ,Antilymphocyte Serum ,Transplantation ,education.field_of_study ,Kidney ,business.industry ,Mesenchymal stem cell ,Antibodies, Monoclonal ,FOXP3 ,medicine.disease ,Kidney Transplantation ,medicine.anatomical_structure ,Immunology ,Kidney Failure, Chronic ,Female ,business ,Immunosuppressive Agents ,CD8 ,medicine.drug - Abstract
Bone marrow-derived mesenchymal stromal cells (MSC) have emerged as useful cell population for immunomodulation therapy in transplantation. Moving this concept towards clinical application, however, should be critically assessed by a tailor-made step-wise approach. Here, we report results of the second step of the multistep MSC-based clinical protocol in kidney transplantation. We examined in two living-related kidney transplant recipients whether: (i) pre-transplant (DAY-1) infusion of autologous MSC protected from the development of acute graft dysfunction previously reported in patients given MSC post-transplant, (ii) avoiding basiliximab in the induction regimen improved the MSC-induced Treg expansion previously reported with therapy including this anti-CD25-antibody. In patient 3, MSC treatment was uneventful and graft function remained normal during 1 year follow-up. In patient 4, acute cellular rejection occurred 2 weeks post-transplant. Both patients had excellent graft function at the last observation. Circulating memory CD8(+) T cells and donor-specific CD8(+) T-cell cytolytic response were reduced in MSC-treated patients, not in transplant controls not given MSC. CD4(+) FoxP3(+) Treg expansion was comparable in MSC-treated patients with or without basiliximab induction. Thus, pre-transplant MSC no longer negatively affect kidney graft at least to the point of impairing graft function, and maintained MSC-immunomodulatory properties. Induction therapy without basiliximab does not offer any advantage on CD4(+) FoxP3(+) Treg expansion (ClinicalTrials.gov number: NCT 00752479).
- Published
- 2013
34. Reconsidering the multi-sports club business model: designing effective new strategies in the face of environmental changes
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Fabio Antoldi, Elisa Capelletti, and Chiara Capelli
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Organizational Behavior and Human Resource Management ,Process management ,Artifact-centric business process model ,Business rule ,05 social sciences ,Strategy ,Product-service system ,Business Model Canvas ,Business model ,Business process modeling ,Environmental change ,General Business, Management and Accounting ,Multi-sports club ,Strategic management ,New business development ,0502 economics and business ,Business analysis ,Business development ,Settore SECS-P/07 - ECONOMIA AZIENDALE ,Economics ,Business development, Strategy, Strategic management, Business model, Environmental change, Multi-sports club ,Marketing ,050203 business & management ,050212 sport, leisure & tourism - Abstract
Purpose This paper aims to discuss the importance of reconsidering the business model in the organizations, to ensure success over time. The paper lies on the analysis and development of the strategies of ten “Società” Canottieri’ – multi-sports clubs in Northern Italy. Design/methodology/approach The strategies of these clubs have been studied via detailed interviews, as well as data and document analysis. Subsequently, two workshops with the management of the clubs were carried out, to collect evidence of the challenges to their sustainability and to identify possible strategies to overcome these challenges. Findings Drawing on Osterwalder’s Business Model Canvas framework and Demil et Lecocq’s approach to business model (a Penrosian approach about the on-going dimension of change as a permanent state of organization), the paper describes how recently emerging issues (external and internal changes) have challenged the traditional business model of these clubs. Finally, authors identify specific actions necessary to (re)create a new value proposition and to modify the sports clubs’ organization in the future, to assure sustainability and success. Originality/value Currently, business model analysis within contexts of (apparent) no economic value creation still remains a relatively unexplored field. The paper describes an effective methodology to implement the business model analysis into a group of independent non-profit organizations. To implement this analysis, the authors adopted the model of Business Model Canvas, but using a transformational and dynamic approach.
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- 2016
35. Thrombospondin-1 promotes mesenchymal stromal cell functions via TGFβ and in cooperation with PDGF
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Martino Introna, Dorina Belotti, Andrea Resovi, Chiara Capelli, and Giulia Taraboletti
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0301 basic medicine ,endocrine system ,Platelet-derived growth factor ,Stromal cell ,medicine.medical_treatment ,Regenerative medicine ,Thrombospondin 1 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Cell Movement ,Transforming Growth Factor beta ,medicine ,Humans ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,Platelet-Derived Growth Factor ,biology ,Growth factor ,Mesenchymal stem cell ,virus diseases ,Mesenchymal Stem Cells ,Transforming growth factor beta ,Cell biology ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,Proteolysis ,biology.protein ,Platelet-derived growth factor receptor ,Protein Binding - Abstract
Mesenchymal stromal cells (MSC) are characterized by unique tropism for wounded tissues, high differentiating capacity, ability to induce tissue repair, and anti-inflammatory and immunoregulatory activities. This has generated interest in their therapeutic use in severe human conditions as well as in regenerative medicine and tissue engineering. Identification of factors involved in the regulation of MSC proliferation, migration and differentiation could provide insights into the pathophysiological regulation of MSC and be exploited to optimize clinical grade expansion protocols for therapeutic use. Here we identify thrombospondin-1 (TSP-1) as a major regulator of MSC. TSP-1 induced MSC proliferation. This effect was mediated by TSP-1-induced activation of endogenous TGFβ, as shown by the inhibitory effects of anti-TGFβ antibodies and by the lack of activity of TSP-2 - that does not activate TGFβ. Moreover, TSP-1 strongly potentiated the proliferative and migratory activity of PDGF on MSC. TSP-1 directly bound to PDGF, through a site located within the TSP-1 type III repeats, and protected the growth factor from degradation by MSC-derived proteases, hence increasing its stability and bioavailability. The studies presented here identify a more comprehensive picture of the pleiotropic effect of TSP-1 on MSC behavior, setting the basis for further studies aimed at investigating the possible use of PDGF and TSP-1 in the in vitro expansion of MSC for therapeutic applications.
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- 2015
36. Minimally manipulated whole human umbilical cord is a rich source of clinical-grade human mesenchymal stromal cells expanded in human platelet lysate
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Andrea Gianatti, Francesco Dazzi, Giovanni Cazzaniga, Alessandro Rambaldi, Chiara Capelli, Martino Introna, Orietta Spinelli, Elisa Gotti, Ling Weng, Cinzia Rota, Marina Morigi, Rosangela Trezzi, and Josée Golay
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Blood Platelets ,Cancer Research ,Pathology ,medicine.medical_specialty ,Cord ,Carcinogenicity Tests ,Immunology ,Graft vs Host Disease ,Mice, SCID ,Biology ,Umbilical cord ,Umbilical Cord ,Mice ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cell Lineage ,Cells, Cultured ,Genetics (clinical) ,Comparative Genomic Hybridization ,Mice, Inbred BALB C ,Transplantation ,Adipogenesis ,Stem Cells ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Fibroblasts ,Culture Media ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Cell culture ,Platelet lysate ,Bone marrow ,Stem cell ,Immunosuppressive Agents ,Blood vessel - Abstract
Mesenchymal stromal cells (MSC) have recently been identified as a therapeutic option in several clinical conditions. Whereas bone marrow (BM) is considered the main source of MSC (BM-MSC), the invasive technique required for collection and the decline in allogeneic donations call for alternative sources. Human umbilical cord (UC) represents an easily available source of MSC (UC-MSC).Sections of full-term UC were transferred to cell culture flasks and cultured in 5% human platelet lysate (PL)-enriched medium. Neither enzymatic digestion nor blood vessel removal was performed. After 2 weeks, the adherent cells were harvested (P1), replated at low density and expanded for two consecutive rounds (P2 and P3).We isolated and expanded MSC from 9/9 UC. UC-MSC expanded with a mean fold increase (FI) of 42 735 ± 16 195 from P1 to P3 in a mean of 29 ± 2 days. By processing the entire cord unit, we theoretically could have reached a median of 9.5 × 10(10) cells (ranging from 1.0 × 10(10) to 29.0 × 10(10)). UC-MSC expressed standard surface markers; they contained more colony-forming unit (CFU)-fibroblast (F) and seemed less committed towards osteogenic, chondrogenic and adipogenic lineages than BM-MSC. They showed immunosuppressive properties both in vitro and in an in vivo chronic Graft versus Host disease (cGvHD) mouse model. Both array-Comparative Genomic Hybridization (CGH) analysis and karyotyping revealed no chromosome alterations at the end of the expansion. Animal studies revealed no tumorigenicity in vivo.UC constitute a convenient and very rich source of MSC for the production of third-party 'clinical doses' of cells under good manufacturing practice (GMP) conditions.
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- 2011
37. Autologous Mesenchymal Stromal Cells and Kidney Transplantation
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Martino Introna, Regiane Aparecida Cavinato, Alessandro Rambaldi, Eliana Gotti, Paola Cassis, Giuseppe Remuzzi, Marina Noris, Maddalena Marasa, Federica Casiraghi, Josée Golay, Marta Todeschini, Chiara Capelli, Monica Cortinovis, Norberto Perico, and Paola Rizzo
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Transplantation Conditioning ,Epidemiology ,Biopsy ,Pilot Projects ,Astrophysics::Cosmology and Extragalactic Astrophysics ,Photoionization ,Astrophysics ,CD8-Positive T-Lymphocytes ,Mesenchymal Stem Cell Transplantation ,Critical Care and Intensive Care Medicine ,T-Lymphocytes, Regulatory ,Transplantation, Autologous ,Spectral line ,Immunophenotyping ,Young Adult ,Thermal ,Living Donors ,medicine ,Humans ,Absorption (electromagnetic radiation) ,Ultraviolet radiation ,Cells, Cultured ,Transplantation ,business.industry ,Quasar ,Original Articles ,Immunohistochemistry ,Kidney Transplantation ,Treatment Outcome ,Nephrology ,Creatinine ,Intergalactic medium ,Feasibility Studies ,Kidney Failure, Chronic ,Drug Therapy, Combination ,business ,Immunologic Memory ,Biomarkers ,Immunosuppressive Agents - Abstract
Mesenchymal stromal cells (MSCs) abrogate alloimmune response in vitro, suggesting a novel cell-based approach in transplantation. Moving this concept toward clinical application in organ transplantation should be critically assessed.A safety and clinical feasibility study (ClinicalTrials.gov, NCT00752479) of autologous MSC infusion was conducted in two recipients of kidneys from living-related donors. Patients were given T cell-depleting induction therapy and maintenance immunosuppression with cyclosporine and mycophenolate mofetil. On day 7 posttransplant, MSCs were administered intravenously. Clinical and immunomonitoring of MSC-treated patients was performed up to day 360 postsurgery.Serum creatinine levels increased 7 to 14 days after cell infusion in both MSC-treated patients. A graft biopsy in patient 2 excluded acute graft rejection, but showed a focal inflammatory infiltrate, mostly granulocytes. In patient 1 protocol biopsy at 1-year posttransplant showed a normal graft. Both MSC-treated patients are in good health with stable graft function. A progressive increase of the percentage of CD4+CD25highFoxP3+CD127- Treg and a marked inhibition of memory CD45RO+RA-CD8+ T cell expansion were observed posttransplant. Patient T cells showed a profound reduction of CD8+ T cell activity.Findings from this study in the two patients show that MSC infusion in kidney transplant recipients is feasible, allows enlargement of Treg in the peripheral blood, and controls memory CD8+ T cell function. Future clinical trials with MSCs to look with the greatest care for unwanted side effects is advised.
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- 2011
38. Platelet-lysate-Expanded Mesenchymal Stromal Cells as a Salvage Therapy for Severe Resistant Graft-versus-Host Disease in a Pediatric Population
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Giovanna D'Amico, Maria Grazia Orofino, J. Golay, Daniela Belotti, Ettore Biagi, Martino Introna, Giuseppe Gaipa, Paolo Perseghin, Attilio Rovelli, Andrea Biondi, Giovanna Lucchini, Sonia Bonanomi, Sarah Marktel, Patrizia Chiusolo, Paola Vinci, Edoardo Lanino, Erica Dander, Alessandro Rambaldi, Agnese Salvadè, Chiara Capelli, Adriana Balduzzi, Lucchini, G, Introna, M, Dander, E, Rovelli, A, Balduzzi, A, Bonanomi, S, Salvadè, A, Capelli, C, Belotti, D, Gaipa, G, Perseghin, P, Vinci, P, Lanino, E, Chiusolo, P, Orofino, M, Marktel, S, Golay, J, Rambaldi, A, Biondi, A, D'Amico, G, and Biagi, E
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Blood Platelets ,Compassionate Use Trials ,Male ,medicine.medical_specialty ,Adolescent ,Bone marrow transplantation ,medicine.medical_treatment ,Mesenchymal stromal cells ,GVHD ,Graft vs Host Disease ,Salvage therapy ,Mesenchymal Stem Cell Transplantation ,Gastroenterology ,Cell therapy ,immune system diseases ,Internal medicine ,medicine ,Humans ,Child ,Salvage Therapy ,Transplantation ,Mesenchymal stromal cell ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Immunosuppression ,Hematology ,medicine.disease ,Surgery ,surgical procedures, operative ,Graft-versus-host disease ,Child, Preschool ,Cord blood ,Female ,Platelet lysate ,Stromal Cells ,business - Abstract
Despite advances in graft-versus-host-disease (GVHD) treatment, it is estimated that overall survival (OS) at 2 years for hematopoietic cell transplantation (HCT) recipients who experience steroid-resistant GVHD is 10%. Among recent therapeutic approaches for GVHD treatment, mesenchymal stromal cells (MSCs) hold a key position. We describe a multicenter experience of 11 pediatric patients diagnosed with acute or chronic GVHD (aGVHD, cGVHD) treated for compassionate use with GMP-grade unrelated HLA-disparate donors' bone marrow-derived MSCs, expanded in platelet-lysate (PL)-containing medium. Eleven patients (aged 4-15 years) received intravenous (i.v.) MSCs for aGVHD or cGVHD, which was resistant to multiple lines of immunosuppression. The median dose was 1.2 x 10(6)/kg (range: 0.7-3.7 x 10(6)/kg). No acute side effects were observed, and no late side effects were reported at a median follow-up of 8 months (range: 4-18 months). Overall response was obtained in 71.4% of patients, with complete response in 23.8% of cases. None of our patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5 months after infusion. Two patients developed chronic limited GVHD. This study underlines the safety of PL-expanded MSC use in children. MSC efficacy seems to be greater in aGVHD than in cGVHD, even after failure of multiple lines of immunosuppression.
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- 2010
39. Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice
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Fiorenza Orlando, Silvia Agarbati, Mauro Provinciali, Armando Gabrielli, Nicoletta Del Papa, A. Grieco, Eleonora Mondini, Chiara Capelli, Martino Introna, Silvia Baroni, C. Tonnini, Stefania Saccomanno, Gianluca Moroncini, Chiara Paolini, and Gaia Goteri
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0301 basic medicine ,Pathology ,Physiology ,Pulmonary Fibrosis ,lcsh:Medicine ,Pathology and Laboratory Medicine ,Biochemistry ,Cell therapy ,Mice ,White Blood Cells ,chemistry.chemical_compound ,0302 clinical medicine ,Animal Cells ,Fibrosis ,Immune Physiology ,Medicine and Health Sciences ,lcsh:Science ,Lung ,Immune Response ,Routes of Administration ,Innate Immune System ,Multidisciplinary ,Animal Models ,respiratory system ,Fetal Blood ,medicine.anatomical_structure ,Experimental Organism Systems ,030220 oncology & carcinogenesis ,Cytokines ,Heterografts ,Female ,Cellular Types ,medicine.symptom ,Research Article ,medicine.medical_specialty ,Immune Cells ,Immunology ,Connective tissue ,Mouse Models ,Inflammation ,Lung injury ,Mesenchymal Stem Cell Transplantation ,Research and Analysis Methods ,Bleomycin ,03 medical and health sciences ,Model Organisms ,Signs and Symptoms ,Diagnostic Medicine ,Intravenous Injections ,medicine ,Animals ,Humans ,Immunohistochemistry Techniques ,Pharmacology ,Blood Cells ,business.industry ,Macrophages ,lcsh:R ,Mesenchymal stem cell ,Biology and Life Sciences ,Proteins ,Mesenchymal Stem Cells ,Cell Biology ,Molecular Development ,medicine.disease ,respiratory tract diseases ,Histochemistry and Cytochemistry Techniques ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Immune System ,Immunologic Techniques ,lcsh:Q ,business ,Collagens ,Developmental Biology - Abstract
Lung fibrosis is a severe condition resulting from several interstial lung diseases (ILD) with different etiologies. Current therapy of ILD, especially those associated with connective tissue diseases, is rather limited and new anti-fibrotic strategies are needed. In this study, we investigated the anti-fibrotic activity in vivo of human mesenchymal stromal cells obtained from whole umbilical cord (hUC-MSC). Adult immunocompetent C57BL/6 mice (n. = 8 for each experimental condition) were injected intravenously with hUC-MSC (n. = 2.5 × 105) twice, 24 hours and 7 days after endotracheal injection of bleomycin. Upon sacrifice at days 8, 14, 21, collagen content, inflammatory cytokine profile, and hUC-MSC presence in explanted lung tissue were analyzed. Systemic administration of a double dose of hUC-MSC significantly reduced bleomycin-induced lung injury (inflammation and fibrosis) in mice through a selective inhibition of the IL6-IL10-TGFβ axis involving lung M2 macrophages. Only few hUC-MSC were detected from explanted lungs, suggesting a “hit and run” mechanism of action of this cellular therapy. Our data indicate that hUC-MSC possess strong in vivo anti-fibrotic activity in a mouse model resembling an immunocompetent human subject affected by inflammatory ILD, providing proof of concept for ad-hoc clinical trials.
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- 2018
40. Clinical grade expansion of MSCs
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Martino Introna, F. Da Roit, O. Pedrini, J. Golay, Chiara Capelli, and R. Valgardsdottir
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Pathology ,medicine.medical_specialty ,Cell type ,Immunology ,Cell Culture Techniques ,Bone Marrow Cells ,Mesenchymal Stem Cell Transplantation ,Immunophenotyping ,Umbilical Cord ,Cell therapy ,chemistry.chemical_compound ,Cell factory ,medicine ,Immunology and Allergy ,Animals ,Humans ,Good manufacturing practice ,Cells, Cultured ,Cell Proliferation ,business.industry ,Mesenchymal stem cell ,Reproducibility of Results ,Clinical grade ,Mesenchymal Stem Cells ,chemistry ,Karyotyping ,Cancer research ,ATMP ,business ,Fetal bovine serum - Abstract
Producing advanced therapy medicinal products (ATMP) according to Good Manufacturing Practice (GMP) guidelines represents a global challenge for the expansion of cells intended for human use. Mesenchymal stromal cells (MSCs) from different sources are one of the most actively developed cell type for a variety of clinical applications in cellular therapy. Complying with GMP means defining accurately both the production process and the release criteria required for a final safe product. We have here reported our manufacturing experience on 103 consecutive clinical-grade in vitro expansions of both bone marrow-derived and umbilical cord-derived mesenchymal stromal cells together with description of methods and reagents utilized in our Cell Factory. The same animal- and serum-free medium, additioned with human platelet lysate, has been used for all the expansions performed. This is the largest experience published so far with this alternative and clinical-grade reagent (compared to the traditional fetal bovine serum) and shows the feasibility and the reproducibility of the method. Indeed, we have been able to produce a sufficient number of MSCs to treat 57 patients so far, enrolled in 7 different experimental phase I/II protocols.
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- 2015
41. Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration
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Martino Introna, Rania M. El Backly, Ranieri Cancedda, Maddalena Mastrogiacomo, Eugenio Patrone, Maria Rosa Todeschi, Antonio Daga, and Chiara Capelli
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Bone Regeneration ,Angiogenesis ,Cell ,Neovascularization, Physiologic ,Biology ,Mesenchymal Stem Cell Transplantation ,Umbilical cord ,Proinflammatory cytokine ,Umbilical Cord ,Neovascularization ,Mice ,Original Research Reports ,medicine ,Animals ,Humans ,Stem Cell Niche ,Bone regeneration ,Cells, Cultured ,Tissue Scaffolds ,Regeneration (biology) ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,Cell biology ,medicine.anatomical_structure ,Immunology ,Female ,medicine.symptom ,Developmental Biology - Abstract
Umbilical cord mesenchymal stem cells (UC-MSCs) show properties similar to bone marrow mesenchymal stem cells (BM-MSCs), although controversial data exist regarding their osteogenic potential. We prepared clinical-grade UC-MSCs from Wharton's Jelly and we investigated if UC-MSCs could be used as substitutes for BM-MSCs in muscoloskeletal regeneration as a more readily available and functional source of MSCs. UC-MSCs were loaded onto scaffolds and implanted subcutaneously (ectopically) and in critical-sized calvarial defects (orthotopically) in mice. For live cell-tracking experiments, UC-MSCs were first transduced with the luciferase gene. Angiogenic properties of UC-MSCs 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-MSCs, contrary to BM-MSCs, 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 proinflammatory/chemotactic cytokine profile than BM-MSCs and a significantly enhanced angiogenic activity. When UC-MSCs were orthotopically transplanted in a calvarial defect, they promoted increased bone formation as well as BM-MSCs. However, at variance with BM-MSCs, 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-MSCs by not depositing bone matrix directly, but acting through the activation of endogenous repair mechanisms.
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- 2015
42. Frequent occurrence of non-malignant genetic alterations in clinical grade mesenchymal stromal cells expanded for cell therapy protocols
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Josée Golay, Olga Pedrini, Alessandro Rambaldi, Martino Introna, Chiara Capelli, Silvia Salmoiraghi, Gisella Cassina, Ursula Giussani, and Orietta Spinelli
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Chromosome Aberrations ,Pathology ,medicine.medical_specialty ,Stromal cell ,Mesenchymal stem cell ,Cell- and Tissue-Based Therapy ,Clinical uses of mesenchymal stem cells ,Genetic Variation ,Non malignant ,Mesenchymal Stem Cells ,Hematology ,Biology ,Mesenchymal Stem Cell Transplantation ,In vitro ,Malignant transformation ,Cell therapy ,medicine ,Humans ,Online Only Articles ,Stem cell transplantation for articular cartilage repair - Abstract
Human bone marrow mesenchymal stromal cells (BM-MSC) represent one of the most investigated “advanced therapeutic medicinal products”.[1][1] Recent safety concerns have focused attention on the possible malignant transformation due to mutations acquired during their large-scale in vitro
- Published
- 2014
43. Molecular events underlying interleukin-6 independence in a subclone of the CMA-03 multiple myeloma cell line
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Donata, Verdelli, Lucia, Nobili, Katia, Todoerti, Laura, Mosca, Sonia, Fabris, Marianna, D'Anca, Elisa, Pellegrino, Roberto, Piva, Giorgio, Inghirami, Chiara, Capelli, Martino, Introna, Luca, Baldini, Raffaella, Chiaramonte, Luigia, Lombardi, and Antonino, Neri
- Subjects
NF-κB pathway ,Interleukin-6 ,MAP Kinase Signaling System ,NF-kappa B ,Apoptosis ,Boronic Acids ,Bortezomib ,multiple myeloma ,STAT3 ,Cell Line, Tumor ,Pyrazines ,Humans ,Transcriptome ,Signal Transduction - Abstract
We explored the molecular mechanisms involved in the establishement of CMA-03/06, an IL-6-independent variant of the multiple myeloma cell line CMA-03 previously generated in our Institution. CMA-03/06 cells grow in the absence of IL-6 with a doubling time comparable with that of CMA-03 cells; neither the addition of IL6 (IL-6) to the culture medium nor co-culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL-6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL-6 independence of CMA-03/06 cells is not apparently due to the development of an autocrine IL-6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA-03/06 cells showed an activated pattern of the NF-κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA-03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA-03/06 cells display a higher sensibility to NF-κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL-6 independence of CMA-03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell-line CMA-03 and its variant CMA-03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL-6-independent growth of myeloma cells.
- Published
- 2014
44. Safe and Effective Treatment of Graft Versus Host Disease with Platelet Lysate-Expanded Mesenchymal Stromal Cells: A Prospective, Multicentric, Phase 1 Study
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Ettore Biagi, Giovanna D`Amico, Giovanna Lucchini, Enrico Pogliani, Andrea Biondi, Attilio Rovelli, Paolo Perseghin, Anna Grassi, Fabio Pavan, Adriana Balduzzi, Erica Dander, Alessandro Rambaldi, Maria Caterina Mico, Alessandra Algarotti, Giuseppe Gaipa, Daniela Belotti, Sara Cortellazzo, Matteo Parma, Sara Deola, Francesca Masciocchi, Chiara Capelli, J. Golay, Martino Introna, and Daniela Longoni
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Pathology ,medicine.medical_specialty ,Transplantation ,Graft-versus-host disease ,business.industry ,Mesenchymal stem cell ,Medicine ,Effective treatment ,Platelet lysate ,Hematology ,business ,medicine.disease - Published
- 2013
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45. Transfer of Growth Factor Receptor mRNA Via Exosomes Unravels the Regenerative Effect of Mesenchymal Stem Cells
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Sara Conti, Marina Morigi, Susanna Tomasoni, Ariela Benigni, Martino Introna, Chiara Capelli, Giuseppe Remuzzi, Lorena Longaretti, Cinzia Rota, and Elisa Gotti
- Subjects
Adult ,Gene Transfer, Horizontal ,Bone Marrow Cells ,Cell Communication ,Biology ,Exosomes ,Kidney Tubules, Proximal ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Growth factor receptor ,Original Research Reports ,Animals ,Humans ,Receptors, Growth Factor ,RNA, Messenger ,Insulin-Like Growth Factor I ,RNA, Small Interfering ,Receptor ,Cells, Cultured ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Messenger RNA ,Cell growth ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,Acute Kidney Injury ,Molecular biology ,Microvesicles ,Mice, Inbred C57BL ,030220 oncology & carcinogenesis ,RNA Interference ,Stem cell ,Developmental Biology ,Homing (hematopoietic) - Abstract
Bone marrow-mesenchymal stem cells (BM-MSC) ameliorate renal dysfunction and repair tubular damage of acute kidney injury by locally releasing growth factors, including the insulin-like growth factor-1 (IGF-1). The restricted homing of BM-MSC at the site of injury led us to investigate a possible gene-based communication mechanism between BM-MSC and tubular cells. Human BM-MSC (hBM-MSC) released microparticles and exosomes (Exo) enriched in mRNAs. A selected pattern of transcripts was detected in Exo versus parental cells. Exo expressed the IGF-1 receptor (IGF-1R), but not IGF-1 mRNA, while hBM-MSC contained both mRNAs. R- cells lacking IGF-1R exposed to hBM-MSC-derived Exo acquired the human IGF-1R transcript that was translated in the corresponding protein. Transfer of IGF-1R mRNA from Exo to cisplatin-damaged proximal tubular cells (proximal tubular epithelial cell [PTEC]) increased PTEC proliferation. Coincubation of damaged PTEC with Exo and soluble IGF-1 further enhanced cell proliferation. These findings suggest that horizontal transfer of the mRNA for IGF-1R to tubular cells through Exo potentiates tubular cell sensitivity to locally produced IGF-1 providing a new mechanism underlying the powerful renoprotection of few BM-MSC observed in vivo.
- Published
- 2012
46. Toward MSC in solid organ transplantation: 2008 position paper of the MISOT study group
- Author
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Pompiliu Piso, H.-D. Volk, Giuseppe Remuzzi, Bart van Hoek, Martino Introna, Sinda Bigenzahn, Hillard M. Lazarus, Norberto Perico, Uta Kunter, E. Eggenhofer, Claudia Lange, Riccardo Saccardi, Robert J. Deans, Martina Seifert, Marina Noris, Federica Casiraghi, Agnes Rosenauer, Carla C. Baan, Felix C. Popp, Amelia Bartholomew, Eliana Gotti, Thomas Wekerle, Dominique Chabannes, Hein W. Verspaget, Przemyslaw Slowik, Martin J. Hoogduijn, Benedetta Mazzanti, Edward K. Geissler, Alessandro Rambaldi, Philipp Renner, Chiara Capelli, Marc H. Dahlke, Hans J. Schlitt, Patrick Bertolino, Internal Medicine, and Epidemiology
- Subjects
Immunosuppression Therapy ,Transplantation ,medicine.medical_specialty ,business.industry ,Mesenchymal stem cell ,Cell- and Tissue-Based Therapy ,Organ Transplantation ,Mesenchymal Stem Cell Transplantation ,Kidney Transplantation ,Surgery ,Liver Transplantation ,Cell therapy ,Clinical trial ,Basic research ,medicine ,Living Donors ,Position paper ,Animals ,Humans ,Solid organ ,Solid organ transplantation ,business ,Immunosuppressive Agents - Abstract
The following position paper summarizes the recommendations for early clinical trials and ongoing basic research in the field of mesenchymal stem cell-induced solid organ graft acceptance--agreed upon on the first meeting of the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late 2008.
- Published
- 2009
47. The washouts of discarded bone marrow collection bags and filters are a very abundant source of hMSCs
- Author
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Piero Bellavita, Agnese Salvadè, Benedetta Cabiati, Olga Pedrini, Valentina Barbui, Paolo Perseghin, Josée Golay, Ettore Biagi, Andrea Biondi, Daniela Belotti, Chiara Capelli, Elisa Gotti, Gianmaria Borleri, Martino Introna, Alessandro Rambaldi, Capelli, C, Salvade, A, Pedrini, O, Barbui, V, Gotti, E, Borleri, G, Cabiati, B, Belotti, D, Perseghin, P, Bellavita, P, Biondi, A, Biagi, E, Rambaldi, A, Golay, J, and Introna, M
- Subjects
Quality Control ,Cancer Research ,Pathology ,medicine.medical_specialty ,Immunology ,Bone Marrow Cells ,Cell Separation ,Biology ,Vial ,Cryopreservation ,Specimen Handling ,Immunophenotyping ,Colony-Forming Units Assay ,medicine ,Immunology and Allergy ,Humans ,Genetics (clinical) ,Cell Proliferation ,Transplantation ,Mesenchymal stem cell ,Hematopoietic stem cell ,Mesenchymal Stem Cells ,Bone Marrow Collection ,Cell Differentiation ,Cell Biology ,medicine.disease ,medicine.anatomical_structure ,Graft-versus-host disease ,Mesenchymal Stem Cell ,Oncology ,Bone Marrow Cell ,Bone marrow ,Filtration - Abstract
BACKGROUND AIMS: Human multipotent mesenchymal stromal cells (hMSC) are considered good candidates for a growing spectrum of cell therapies. We have validated a protocol that makes use of the washouts of discarded collection sets, left over at the end of the filtration of bone marrow (BM) explants performed for hematopoietic stem cell (HSC) transplantation. METHODS: The method consists of direct plating of cells without density-gradient isolation followed by two detachment steps and expansion in 5% human platelet lysate (hPL). RESULTS: In a median of 26 days, 14 bags for adult patients and nine bags for pediatric patients for a standard dose of 1x10(6) hMSC/kg body weight could be prepared from the expansion of a fraction of the cells recovered from seven independent washouts. Moreover, 151 vials could be frozen from the remaining cells. The theoretical full expansion of all the frozen vials (validated by the expansion of two independent vials) could have allowed the production of 173 bags for adults and 348 bags for pediatric patients. CONCLUSIONS: The washouts of discarded bags and filters left over at the end of routine BM explants filtration are a very abundant source of hMSC precursors that can be easily utilized for clinical applications.
- Published
- 2009
48. Human platelet lysate allows expansion and clinical grade production of mesenchymal stromal cells from small samples of bone marrow aspirates or marrow filter washouts
- Author
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Josée Golay, Gianmaria Borleri, Martino Introna, Caterina Micò, Chiara Capelli, Bellavita P, M Domenghini, Alessandra Carobbio, Alessandro Rambaldi, and R Poma
- Subjects
Blood Platelets ,Pathology ,medicine.medical_specialty ,Stromal cell ,Cell Culture Techniques ,Bone Marrow Cells ,Biology ,Andrology ,Internal medicine ,medicine ,Humans ,Platelet ,Cell Proliferation ,Transplantation ,Hematology ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,equipment and supplies ,Mixed lymphocyte reaction ,Culture Media ,medicine.anatomical_structure ,Platelet lysate ,Bone marrow ,Fetal bovine serum - Abstract
We compared two protocols for the expansion of human mesenchymal stromal cells (hMSCs) starting from diagnostic samples of BM aspirates (2-5 ml) or using the remnants in the bag and filter at the end of the BM infusions. The protocols differed in the presence of either 10% fetal bovine serum (FBS) or 5% platelet lysate (PL). We obtained a significantly (P=0.02) better expansion with PL, obtaining a median 1010-fold compared to 198-fold with a selected batch of FBS and in fewer days (29.8 in PL versus 41.4 in FBS). Overall, we recovered a variable number from 54.8 x 10(6) to 365 x 10(6) hMSCs in PL versus a variable number from 2.7 x 10(6) to 31 x 10(6) in FBS. No difference could be found in terms of gross morphology, differentiation potential, surface markers and immunological properties (inhibition of allogeneic PHA response and mixed lymphocyte reaction) of cells expanded with PL or FBS. The preparations were found within the range of acceptability for all the quality control criteria. Due to the clinical grade nature of the PL and the reproducibility of separate preparations, we propose this method to obtain hMSCs even from minute amounts of BM cells.
- Published
- 2007
49. Immunomonitoring of Transplanted Patients Infused With Mesenchymal Stromal Cells (MSC) for Treating Steroid-Refractory GVHD
- Author
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Martino Introna, Chiara Capelli, J. Golay, F. Masciocchi, Ettore Biagi, Giuseppe Gaipa, Sonia Bonanomi, Giovanna D'Amico, Paola Vinci, Andrea Biondi, Paolo Perseghin, Erica Dander, Attilio Rovelli, Alessandra Algarotti, Adriana Balduzzi, Alessandro Rambaldi, and Giovanna Lucchini
- Subjects
Transplantation ,business.industry ,Mesenchymal stem cell ,Cancer research ,Medicine ,Hematology ,Steroid refractory ,business - Published
- 2011
50. THU0066 Phenotypical and Functional Characteristics of in Vitro Expanded Adipose-Derived Mesenchymal Stem Cells from Patients with Systemic Sclerosis
- Author
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Eleonora Zaccara, Martino Introna, Riccardo Polosa, Fabio Caviggioli, N. Del Papa, Domenico Sambataro, Marco Klinger, Chiara Capelli, Valeriano Vinci, and Wanda Maglione
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Immunology ,Mesenchymal stem cell ,CD34 ,Adipose tissue ,Lymphocyte proliferation ,General Biochemistry, Genetics and Molecular Biology ,medicine.anatomical_structure ,Rheumatology ,Immunology and Allergy ,Medicine ,CD90 ,Bone marrow ,Stem cell ,business ,Adult stem cell - Abstract
Background Adult stem cells, expecially those of mesodermal origin (MSCs), have received attention as an ideal source of regenerative capable cells because of their multipotentially and ability to replicate. Regenerative cells from the bone marrow, peripheral blood, and umbilical cord blood have been used to treat a variety of diseases. Adipose tissue is an attractive source of adult stem cells due to its abundance and surgical accessibility. Recent studies have shown the efficacy of the autologous fat grafting in the treatment of different skin diseases including localized scleroderma and ischemic diseases. Objectives We characterized phenotypically and functionally adipose tissue-derived mesenchymal stem cells (ADMSCs) from patients with Systemic Sclerosis (SSc). Methods Human adipose tissue samples were obtained from 10 patients with the diffuse form of SSc (dcSSc) undergoing autologous lipostructure for the treatment of fibrotic perioral changes. As controls, adipose tissue samples were obtained from 10 healthy donors (HD) undergoing aesthetic surgery. Lipoaspirate tissue was collected from elective liposuction procedures and processed by both explant and enzymatic methods. Key parameters of ADMSCs function and phenotype were assessed including the ability to: express cell surface antigens defining the MSC population (CD105, CD73, CD29, CD90, CD44 marker profile was examined by FACS analysis), proliferate (growth kinetics assay), differentiate along the adipogenic and osteogenic lineages, suppress in vitro lymphocyte proliferation induced by the mixed lymphocyte reaction. Results Cultured ADMSCs obtained from the processing of adipose tissue showed no significant differences in morphology and in proliferation rate in the culture conditions used. Phenotypically, SSc ADMSCs highly expressed CD105, CD73, CD90, HLA-ABC and were mostly negative for HLA-DR expression. The absence of contaminating hematopoietic stem cells was confirmed by the negative expression of CD34, CD14 and CD45 antigens in all studied cases. No phenotypic differences were observed between ADMSCs from patients with SSc and controls. When cultured in standard induction medium, all SSc and HD ADMSCs differentiated toward the osteogenic and adipogenic lineages. In MLR assays, no significant differences in ADMSCs mediated inhibition of proliferation were observed between SSc patients and controls. Conclusions Autologous adipose graft could be a new therapeutic option for the treatment of skin diseases such as SSc. The mechanisms through which adipose tissue exerts its therapeutic potential in tissue repair is not yet fully defined, but it might be related to the well known ability of MSCs to modulate inflammatory and autoimmune process, secrete soluble factors capable to stimulate functional recovery of injured cells and differentiate into other cell types. The results of our study show that ADMSCs from patients with SSc exhibit the same phenotypic, proliferative, differentiation potential and immunosoppressive properties as HD. Further studies are need to clarify the ADMSCs specific contribution to the clinically relevant benefits in SSc soft-tissue reconstruction. Disclosure of Interest None Declared
- Published
- 2013
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