37 results on '"Lucio Barile"'
Search Results
2. Supervised and unsupervised learning to define the cardiovascular risk of patients according to an extracellular vesicle molecular signature
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Jacopo Burrello, Alessio Burrello, Elena Vacchi, Giovanni Bianco, Elena Caporali, Martina Amongero, Lorenzo Airale, Sara Bolis, Giuseppe Vassalli, Carlo W. Cereda, Paolo Mulatero, Benedetta Bussolati, Giovanni G. Camici, Giorgia Melli, Silvia Monticone, Lucio Barile, University of Zurich, and Barile, Lucio
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Physiology ,610 Medicine & health ,2704 Biochemistry (medical) ,Machine Learning ,11459 Center for Molecular Cardiology ,Extracellular Vesicles ,2737 Physiology (medical) ,Risk Factors ,Physiology (medical) ,Internal Medicine ,Humans ,Heart Failure ,Biochemistry (medical) ,Environmental and Occupational Health ,Public Health, Environmental and Occupational Health ,Biomarker ,2739 Public Health, Environmental and Occupational Health ,General Medicine ,Cross-Sectional Studies ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Hypertension ,Cardiovascular Risk ,570 Life sciences ,biology ,Public Health ,Cardiology and Cardiovascular Medicine ,Biomarkers ,Unsupervised Machine Learning - Abstract
Cardiovascular (CV) disease represents the most common cause of death in developed countries. Risk assessment is highly relevant to intervene at individual level and implement prevention strategies. Circulating extracellular vesicles (EVs) are involved in the development and progression of CV diseases and are considered promising biomarkers. We aimed at identifying an EV signature to improve the stratification of patients according to CV risk and likelihood to develop fatal CV events. EVs were characterized by nanoparticle tracking analysis and flow cytometry for a standardized panel of 37 surface antigens in a cross-sectional multicenter cohort (n = 486). CV profile was defined by presence of different indicators (age, sex, body mass index, hypertension, hyperlipidemia, diabetes, coronary artery disease, cardiac heart failure, chronic kidney disease, smoking habit, organ damage) and according to the 10-year risk of fatal CV events estimated using SCORE charts of European Society of Cardiology. By combining expression levels of EV antigens using unsupervised learning, patients were classified into 3 clusters: Cluster-I (n = 288), Cluster-II (n = 83), Cluster-III (n = 30). A separate analysis was conducted on patients displaying acute CV events (n = 82). Prevalence of hypertension, diabetes, chronic heart failure, and organ damage (defined as left ventricular hypertrophy and/or microalbuminuria) increased progressively from Cluster-I to Cluster-III. Several EV antigens, including markers for platelets (CD41b-CD42a-CD62P), leukocytes (CD1c-CD2-CD3-CD4-CD8-CD14-CD19-CD20-CD25-CD40-CD45-CD69-CD86), and endothelium (CD31-CD105) were independently associated with CV risk indicators and correlated to age, blood pressure, glucometabolic profile, renal function, and SCORE risk. EV profiling, obtained from minimally invasive blood sampling, allows accurate patient stratification according to CV risk profile.
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- 2022
3. An extracellular vesicle epitope profile is associated with acute myocardial infarction
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Silvia Monticone, Jacopo Burrello, Elena Caporali, Elena Provasi, Giuseppe Vassalli, Carolina Balbi, Lucio Barile, Andrea Peirone, Sara Bolis, Alessio Burrello, Lorenzo Grazioli Gauthier, Fabrizio D'Ascenzo, University of Zurich, Burrello, Jacopo, and Vassalli, Giuseppe
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0301 basic medicine ,Male ,Integrin alpha2 ,acute myocardial infarction ,biomarker ,coronary artery disease ,extracellular vesicles ,machine learning ,ST-segment elevation myocardial infarction ,Coronary artery disease ,1307 Cell Biology ,Cohort Studies ,Epitopes ,0302 clinical medicine ,Medicine ,Myocardial infarction ,biology ,medicine.diagnostic_test ,Extracellular vesicle ,Middle Aged ,Platelet Endothelial Cell Adhesion Molecule-1 ,P-Selectin ,Platelet Glycoprotein GPIb-IX Complex ,030220 oncology & carcinogenesis ,Cohort ,Cardiology ,Biomarker (medicine) ,Molecular Medicine ,Original Article ,Female ,medicine.medical_specialty ,610 Medicine & health ,11171 Cardiocentro Ticino ,Flow cytometry ,03 medical and health sciences ,Extracellular Vesicles ,Percutaneous Coronary Intervention ,Internal medicine ,ST‐segment elevation myocardial infarction ,Humans ,Angina, Stable ,Acute Coronary Syndrome ,CD40 Antigens ,Aged ,business.industry ,Cell Biology ,Original Articles ,medicine.disease ,Troponin ,Molecular medicine ,030104 developmental biology ,1313 Molecular Medicine ,biology.protein ,ST Elevation Myocardial Infarction ,business ,Biomarkers ,Epitope Mapping - Abstract
The current standard biomarker for myocardial infarction (MI) is high‐sensitive troponin. Although powerful in clinical setting, search for new markers is warranted as early diagnosis of MI is associated with improved outcomes. Extracellular vesicles (EVs) attracted considerable interest as new blood biomarkers. A training cohort used for diagnostic modelling included 30 patients with STEMI, 38 with stable angina (SA) and 30 matched‐controls. Extracellular vesicle concentration was assessed by nanoparticle tracking analysis. Extracellular vesicle surface‐epitopes were measured by flow cytometry. Diagnostic models were developed using machine learning algorithms and validated on an independent cohort of 80 patients. Serum EV concentration from STEMI patients was increased as compared to controls and SA. EV levels of CD62P, CD42a, CD41b, CD31 and CD40 increased in STEMI, and to a lesser extent in SA patients. An aggregate marker including EV concentration and CD62P/CD42a levels achieved non‐inferiority to troponin, discriminating STEMI from controls (AUC = 0.969). A random forest model based on EV biomarkers discriminated the two groups with 100% accuracy. EV markers and RF model confirmed high diagnostic performance at validation. In conclusion, patients with acute MI or SA exhibit characteristic EV biomarker profiles. EV biomarkers hold great potential as early markers for the management of patients with MI.
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- 2020
4. Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies
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Elena Vacchi, Edoardo Lazzarini, Sandra Pinton, Giacomo Chiaro, Giulio Disanto, Francesco Marchi, Thomas Robert, Claudio Staedler, Salvatore Galati, Claudio Gobbi, Lucio Barile, Alain Kaelin-Lang, and Giorgia Melli
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Synucleinopathies ,Tauopathies ,Biopsy ,Humans ,Parkinson Disease ,tau Proteins ,610 Medicine & health ,Supranuclear Palsy, Progressive ,Neurology (clinical) ,Multiple System Atrophy ,eye diseases - Abstract
Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological τ has also been observed in α-synucleinopathies like Parkinson’s disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibres in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 kDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total τ protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson’s disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiological and pathological conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.
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- 2022
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5. Profiling Inflammatory Extracellular Vesicles in Plasma and Cerebrospinal Fluid: An Optimized Diagnostic Model for Parkinson's Disease
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Alain Kaelin-Lang, Silvia Monticone, Jacopo Burrello, Elena Vacchi, Giorgia Melli, Lucio Barile, Sara Bolis, and Alessio Burrello
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Pathology ,medicine.medical_specialty ,Parkinson's disease ,multiple system atrophy ,Medicine (miscellaneous) ,Inflammation ,610 Medicine & health ,Extracellular vesicles ,General Biochemistry, Genetics and Molecular Biology ,Article ,cerebrospinal fluid ,neuroinflammation ,Immune system ,Atrophy ,Cerebrospinal fluid ,Medicine ,lcsh:QH301-705.5 ,Neuroinflammation ,plasma ,business.industry ,tauopathies ,biomarkers ,medicine.disease ,machine learning ,lcsh:Biology (General) ,Parkinson’s disease ,extracellular vesicles ,medicine.symptom ,business ,Intracellular - Abstract
Extracellular vesicles (EVs) play a central role in intercellular communication, which is relevant for inflammatory and immune processes implicated in neurodegenerative disorders, such as Parkinson’s Disease (PD). We characterized and compared distinctive cerebrospinal fluid (CSF)-derived EVs in PD and atypical parkinsonisms (AP), aiming to integrate a diagnostic model based on immune profiling of plasma-derived EVs via artificial intelligence. Plasma- and CSF-derived EVs were isolated from patients with PD, multiple system atrophy (MSA), AP with tauopathies (AP-Tau), and healthy controls. Expression levels of 37 EV surface markers were measured by a flow cytometric bead-based platform and a diagnostic model based on expression of EV surface markers was built by supervised learning algorithms. The PD group showed higher amount of CSF-derived EVs than other groups. Among the 17 EV surface markers differentially expressed in plasma, eight were expressed also in CSF of a subgroup of PD, 10 in MSA, and 6 in AP-Tau. A two-level random forest model was built using EV markers co-expressed in plasma and CSF. The model discriminated PD from non-PD patients with high sensitivity (96.6%) and accuracy (92.6%). EV surface marker characterization bolsters the relevance of inflammation in PD and it underscores the role of EVs as pathways/biomarkers for protein aggregation-related neurodegenerative diseases.
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- 2021
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6. Cardiac Graft Assessment in the Era of Machine Perfusion: Current and Future Biomarkers
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Sarah L. Longnus, Thierry Carrel, Natalia Méndez-Carmona, Dominik Günsch, Maria Arnold, Maria N. Sanz, Lucio Barile, Martina Bona, and Rahel K. Wyss
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medicine.medical_specialty ,medicine.medical_treatment ,Ischemia ,610 Medicine & health ,donation after circulatory death ,030204 cardiovascular system & hematology ,030230 surgery ,heart transplantation ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Diseases of the circulatory (Cardiovascular) system ,extended‐criteria heart donors ,Intensive care medicine ,Heart transplantation ,Machine perfusion ,business.industry ,biomarkers ,ex situ heart perfusion ,medicine.disease ,Circulatory death ,Transplantation ,Heart failure ,Potential biomarkers ,Donation ,RC666-701 ,Cardiology and Cardiovascular Medicine ,business - Abstract
Heart transplantation remains the treatment of reference for patients experiencing end‐stage heart failure; unfortunately, graft availability through conventional donation after brain death is insufficient to meet the demand. Use of extended‐criteria donors or donation after circulatory death has emerged to increase organ availability; however, clinical protocols require optimization to limit or prevent damage in hearts possessing greater susceptibility to injury than conventional grafts. The emergence of cardiac ex situ machine perfusion not only facilitates the use of extended‐criteria donor and donation after circulatory death hearts through the avoidance of potentially damaging ischemia during graft storage and transport, it also opens the door to multiple opportunities for more sensitive monitoring of graft quality. With this review, we aim to bring together the current knowledge of biomarkers that hold particular promise for cardiac graft evaluation to improve precision and reliability in the identification of hearts for transplantation, thereby facilitating the safe increase in graft availability. Information about the utility of potential biomarkers was categorized into 5 themes: (1) functional, (2) metabolic, (3) hormone/prohormone, (4) cellular damage/death, and (5) inflammatory markers. Several promising biomarkers are identified, and recommendations for potential improvements to current clinical protocols are provided.
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- 2021
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7. Perioperative cardioprotection: back to bedside
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Lucio Barile, Vincenzo Lionetti, University of Zurich, and Lionetti, Vincenzo
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medicine.medical_specialty ,Myocardial Infarction ,Myocardial Ischemia ,Ischemia ,610 Medicine & health ,Perioperative, cardioprotection, translational research, exosomes ,exosomes ,11171 Cardiocentro Ticino ,law.invention ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Randomized controlled trial ,Risk Factors ,030202 anesthesiology ,law ,Humans ,Medicine ,Perioperative ,Myocardial infarction ,Cardiac Surgical Procedures ,Intensive care medicine ,Polypharmacy ,Cardioprotection ,business.industry ,030208 emergency & critical care medicine ,medicine.disease ,Cardiac surgery ,Anesthesiology and Pain Medicine ,translational research ,Elective Surgical Procedures ,cardioprotection ,2703 Anesthesiology and Pain Medicine ,business ,Reperfusion injury - Abstract
Over the last 20 years, an increasing number of patients with multimorbidity and polypharmacy underwent different types of elective non-cardiac and cardiac surgery. Despite surgery is safer today than in the past, rate of perioperative major adverse cardiovascular events is still attracting significant attention from both clinicians and researchers. The perioperative myocardial infarction (PMI), a permanent damage of the heart, is a major cause of short- and long-term morbidity and mortality in current surgical populations. Although it is primarily the result of local myocardial ischemia during major noncardiac surgery, high-risk patients undergoing cardiac surgery are also susceptible to PMI following an acute global ischemia/reperfusion injury. Since recent large-scale randomized controlled trials revealed the poor perioperative effectiveness of some available medications, it is conceivable that deeper clarification of adaptive response pathways of cardiac cells to perioperative myocardial injury would be appropriate to develop approaches that enhance cardioprotection in both surgery types. Indeed, solid preclinical data have highlighted the role of non-myocyte cells in promoting earlier cardiomyocytes survival in an epigenetic manner. These findings challenge our view of what may be feasible in terms of perioperative cardioprotection, despite technological limitations. Here, we will first analyze recent large-scale trials regarding current cardioprotective aids in non-cardiac and cardiac surgery. Finally, we will review novel cardioprotective targets translatable to surgical patients.
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- 2020
8. Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation
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Carolina Balbi, Lucio Barile, Sveva Bollini, Ambra Costa, and University of Zurich
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0301 basic medicine ,Heart disease ,myocardial renewal ,610 Medicine & health ,Review ,exosomes ,2700 General Medicine ,030204 cardiovascular system & hematology ,Regenerative medicine ,11171 Cardiocentro Ticino ,Extracellular Vesicles ,angiogenesis ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,medicine ,Animals ,Humans ,Rejuvenation ,Myocytes, Cardiac ,Progenitor cell ,lcsh:QH301-705.5 ,paracrine effect ,Mechanism (biology) ,business.industry ,Myocardium ,Stem Cells ,Regeneration (biology) ,cardiac repair ,extracellular vesicles ,regeneration ,General Medicine ,medicine.disease ,Microvesicles ,030104 developmental biology ,lcsh:Biology (General) ,Stem cell ,business ,Neuroscience - Abstract
Ischaemic cardiac disease is associated with a loss of cardiomyocytes and an intrinsic lack of myocardial renewal. Recent work has shown that the heart retains limited cardiomyocyte proliferation, which remains inefficient when facing pathological conditions. While broadly active in the neonatal mammalian heart, this mechanism becomes quiescent soon after birth, suggesting loss of regenerative potential with maturation into adulthood. A key question is whether this temporary regenerative window can be enhanced via appropriate stimulation and further extended. Recently the search for novel therapeutic approaches for heart disease has centred on stem cell biology. The “paracrine effect” has been proposed as a promising strategy to boost endogenous reparative and regenerative mechanisms from within the cardiac tissue by exploiting the modulatory potential of soluble stem cell-secreted factors. As such, growing interest has been specifically addressed towards stem/progenitor cell-secreted extracellular vesicles (EVs), which can be easily isolated in vitro from cell-conditioned medium. This review will provide a comprehensive overview of the current paradigm on cardiac repair and regeneration, with a specific focus on the role and mechanism(s) of paracrine action of EVs from cardiac stromal progenitors as compared to exogenous stem cells in order to discuss the optimal choice for future therapy. In addition, the challenges to overcoming translational EV biology from bench to bedside for future cardiac regenerative medicine will be discussed.
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- 2020
9. Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro
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Angela Papa, Regina Fritsche-Danielson, Lucio Barile, Valentina Casieri, Emilio M. Pasanisi, Vincenzo Lionetti, Marco Matteucci, University of Zurich, and Lionetti, Vincenzo
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0301 basic medicine ,Cell biology ,Ticagrelor ,MAP Kinase Signaling System ,cardiac progenitor cells ,lcsh:Medicine ,Apoptosis ,610 Medicine & health ,030204 cardiovascular system & hematology ,Exosomes ,Exosome ,Article ,11171 Cardiocentro Ticino ,Mice ,03 medical and health sciences ,0302 clinical medicine ,P2Y12 ,Aurora Kinases ,medicine ,Animals ,Humans ,HSP70 Heat-Shock Proteins ,Myocytes, Cardiac ,Progenitor cell ,lcsh:Science ,Cells, Cultured ,Aged ,Cell Proliferation ,Cardioprotection ,1000 Multidisciplinary ,Multidisciplinary ,Molecular medicine ,Cell growth ,Chemistry ,lcsh:R ,Mesenchymal stem cell ,Cell Hypoxia ,Microvesicles ,exosomes, cardioprotection, cardiac progenitor cells, ticagrelor ,030104 developmental biology ,cardioprotection ,Purinergic P2Y Receptor Antagonists ,lcsh:Q ,medicine.drug - Abstract
Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hCPCs) is regulated by clinically relevant dose of ticagrelor (1 μM), an oral selective and reversible non-thienopyridine P2Y12 inhibitor. Ticagrelor-induced enhancement of exosome levels is related to increased mitotic activity of hCPCs. We show a drug-response threshold above which the effects on hCPCs are lost due to higher dose of ticagrelor and larger adenosine levels. While it is known that pan-Aurora kinase inhibitor halts cell proliferation through dephosphorylation of histone H3 residue Ser10, we demonstrate that it also prevents ticagrelor-induced effects on release of cardiac progenitor cell-derived exosomes delivering anti-apoptotic HSP70. Indeed, sustained pre-treatment of cardiomyocytes with exosomes released from explant-derived hCPCs exposed to low-dose ticagrelor attenuated hypoxia-induced apoptosis through acute phosphorylation of ERK42/44. Our data indicate that ticagrelor can be leveraged to modulate release of anti-hypoxic exosomes from resident hCPCs.
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- 2020
10. Circulating extracellular vesicles as non-invasive biomarker of rejection in heart transplant
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Giuseppe Vassalli, Gino Gerosa, Lucio Barile, Marny Fedrigo, Alessio Burrello, Tomaso Bottio, Gaetano Thiene, Cristina Basso, Vanessa Biemmi, Giuseppe Toscano, Sara Bolis, Sarah L. Longnus, Jacopo Burrello, Dario Di Silvestre, Francesco Tona, Annalisa Angelini, Chiara Castellani, University of Zurich, Angelini, Annalisa, and Barile, Lucio
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Adult ,Graft Rejection ,Male ,Pathology ,medicine.medical_specialty ,2747 Transplantation ,Biopsy ,610 Medicine & health ,Human leukocyte antigen ,030204 cardiovascular system & hematology ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,medicine ,Humans ,Multiplex ,heart transplant ,Aged ,Transplantation ,medicine.diagnostic_test ,Receiver operating characteristic ,allograft rejection ,biomarker ,extracellular vesicles ,machine learning ,business.industry ,Area under the curve ,Middle Aged ,Allografts ,Flow Cytometry ,2746 Surgery ,3. Good health ,030104 developmental biology ,ROC Curve ,2740 Pulmonary and Respiratory Medicine ,Biomarker (medicine) ,Heart Transplantation ,Surgery ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Background: Circulating extracellular vesicles (EVs) are raising considerable interest as a non-invasive diagnostic tool, as they are easily detectable in biologic fluids and contain a specific set of nucleic acids, proteins, and lipids reflecting pathophysiologic conditions. We aimed to investigate differences in plasma-derived EV surface protein profiles as a biomarker to be used in combination with endomyocardial biopsies (EMBs) for the diagnosis of allograft rejection. Methods: Plasma was collected from 90 patients (53 training cohort, 37 validation cohort) before EMB. EV concentration was assessed by nanoparticle tracking analysis. EV surface antigens were measured using a multiplex flow cytometry assay composed of 37 fluorescently labeled capture bead populations coated with specific antibodies directed against respective EV surface epitopes. Results: The concentration of EVs was significantly increased and their diameter decreased in patients undergoing rejection as compared with negative ones. The trend was highly significant for both antibody-mediated rejection and acute cellular rejection (p < 0.001). Among EV surface markers, CD3, CD2, ROR1, SSEA-4, human leukocyte antigen (HLA)-I, and CD41b were identified as discriminants between controls and acute cellular rejection, whereas HLA-II, CD326, CD19, CD25, CD20, ROR1, SSEA-4, HLA-I, and CD41b discriminated controls from patients with antibody-mediated rejection. Receiver operating characteristics curves confirmed a reliable diagnostic performance for each single marker (area under the curve range, 0.727-0.939). According to differential EV-marker expression, a diagnostic model was built and validated in an external cohort of patients. Our model was able to distinguish patients undergoing rejection from those without rejection. The accuracy at validation in an independent external cohort reached 86.5%. Its application for patient management has the potential to reduce the number of EMBs. Further studies in a higher number of patients are required to validate this approach for clinical purposes. Conclusions: Circulating EVs are highly promising as a new tool to characterize cardiac allograft rejection and to be complementary to EMB monitoring.
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- 2020
11. Sphingolipid composition of circulating extracellular vesicles after myocardial ischemia
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Jacopo Burrello, Vanessa Biemmi, Sveva Bollini, Sara Bolis, M. Dei Cas, Edoardo Lazzarini, Martina Amongero, Lucio Barile, Rita Paroni, G. Vassalli, University of Zurich, and Barile, L
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Male ,0301 basic medicine ,medicine.medical_treatment ,Myocardial Ischemia ,lcsh:Medicine ,Pilot Projects ,610 Medicine & health ,030204 cardiovascular system & hematology ,Pharmacology ,11171 Cardiocentro Ticino ,Diagnosis, Differential ,Cell membrane ,Extracellular Vesicles ,Leukocyte Count ,03 medical and health sciences ,Percutaneous Coronary Intervention ,0302 clinical medicine ,Tandem Mass Spectrometry ,medicine ,Humans ,Myocardial infarction ,cardiovascular diseases ,Lipid bilayer ,lcsh:Science ,Aged ,Sphingolipids ,1000 Multidisciplinary ,Multidisciplinary ,Ejection fraction ,Chemistry ,lcsh:R ,Percutaneous coronary intervention ,Middle Aged ,medicine.disease ,Sphingolipid ,030104 developmental biology ,medicine.anatomical_structure ,ST Elevation Myocardial Infarction ,Female ,Composition (visual arts) ,lipids (amino acids, peptides, and proteins) ,lcsh:Q ,Sphingomyelin ,Biomarkers ,Chromatography, Liquid - Abstract
Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling. Extracellular vesicles (EV) are lipid bilayer membrane nanoparticle and their lipid composition may be different from parental cells, with a significant enrichment in sphingolipid species, especially in pathological conditions. We aimed at optimizing EV isolation from plasma and describing the differential lipid content of EV, as compared to whole plasma. As pilot study, we evaluated the diagnostic potential of lipidomic signature of circulating EV in patients with a diagnosis of ST-segment-elevation myocardial infarction (STEMI). STEMI patients were evaluated before reperfusion and 24-h after primary percutaneous coronary intervention. Twenty sphingolipid species were quantified by liquid-chromatography tandem-mass-spectrometry. EV-ceramides, -dihydroceramides, and -sphingomyelins increased in STEMI vs. matched controls and decreased after reperfusion. Their levels correlated to hs-troponin, leucocyte count, and ejection fraction. Plasma sphingolipids levels were 500-to-700-fold higher as compared to EV content; nevertheless, only sphingomyelins differed in STEMI vs. control patients. Different sphingolipid species were enriched in EV and their linear combination by machine learning algorithms accurately classified STEMI patients at pre-PCI evaluation. In conclusion, EV lipid signature discriminates STEMI patients. These findings may contribute to the identification of novel biomarkers and signaling mechanisms related to cardiac ischemia.
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- 2020
12. Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury
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Kåre-Olav Stensløkken, David Garcia-Dorado, Lucio Barile, Sean M. Davidson, Adriana Adameova, Antigone Lazou, Pasquale Pagliaro, Hector A. Cabrera-Fuentes, University of Zurich, and Davidson, Sean M
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0301 basic medicine ,Apoptosis ,Review ,Ischaemia ,necrosis ,1307 Cell Biology ,0302 clinical medicine ,apoptosis ,autophagy ,cardiac ,cell death ,ischaemia ,myocardial infarction ,necroptosis ,pyroptosis ,reperfusion ,Mitophagy ,Medicine ,media_common ,Cardioprotection ,Pyroptosis ,Cell biology ,Mitochondria ,030220 oncology & carcinogenesis ,Necroptosis ,Molecular Medicine ,Cardiac ,Signal Transduction ,Cell death ,Programmed cell death ,Reviews ,610 Medicine & health ,Myocardial Reperfusion Injury ,11171 Cardiocentro Ticino ,03 medical and health sciences ,Necrosis ,Autophagy ,media_common.cataloged_instance ,Humans ,European union ,business.industry ,Myocardium ,Cell Biology ,Myocardial infarction ,030104 developmental biology ,Mitochondrial permeability transition pore ,1313 Molecular Medicine ,Reperfusion ,business - Abstract
Acute myocardial infarction causes lethal injury to cardiomyocytes during both ischaemia and reperfusion (IR). It is important to define the precise mechanisms by which they die in order to develop strategies to protect the heart from IR injury. Necrosis is known to play a major role in myocardial IR injury. There is also evidence for significant myocardial death by other pathways such as apoptosis, although this has been challenged. Mitochondria play a central role in both of these pathways of cell death, as either a causal mechanism is the case of mitochondrial permeability transition leading to necrosis, or as part of the signalling pathway in mitochondrial cytochrome c release and apoptosis. Autophagy may impact this process by removing dysfunctional proteins or even entire mitochondria through a process called mitophagy. More recently, roles for other programmed mechanisms of cell death such as necroptosis and pyroptosis have been described, and inhibitors of these pathways have been shown to be cardioprotective. In this review, we discuss both mitochondrial and mitochondrial‐independent pathways of the major modes of cell death, their role in IR injury and their potential to be targeted as part of a cardioprotective strategy. This article is part of a special Issue entitled ‘Mitochondria as targets of acute cardioprotection’ and emerged as part of the discussions of the European Union (EU)‐CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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- 2020
13. Exosomes: Therapy delivery tools and biomarkers of diseases
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Giuseppe Vassalli, Lucio Barile, University of Zurich, and Barile, Lucio
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0301 basic medicine ,Small RNA ,Cell signaling ,Endosome ,610 Medicine & health ,Cell Communication ,Biology ,Exosomes ,Exosome ,11171 Cardiocentro Ticino ,03 medical and health sciences ,Drug Delivery Systems ,Animals ,Humans ,2736 Pharmacology (medical) ,Tissue Distribution ,Pharmacology (medical) ,Secretion ,Pharmacology ,Microvesicle ,Gene Transfer Techniques ,Microvesicles ,3. Good health ,Cell biology ,3004 Pharmacology ,030104 developmental biology ,Liposomes ,Immunology ,Drug delivery ,Nanoparticles ,RNA ,Biomarkers - Abstract
Virtually all cells in the organism secrete extracellular vesicles (EVs), a heterogeneous population of lipid bilayer membrane-enclosed vesicles that transport and deliver payloads of proteins and nucleic acids to recipient cells, thus playing central roles in cell-cell communications. Exosomes, nanosized EVs of endosomal origin, regulate many pathophysiological processes including immune responses and inflammation, tumour growth, and infection. Healthy subjects and patients with different diseases release exosomes with different RNA and protein contents into the circulation, which can be measured as biomarkers. The discovery of exosomes as natural carriers of functional small RNA and proteins has raised great interest in the drug delivery field, as it may be possible to harness these vesicles for therapeutic delivery of miRNA, siRNA, mRNA, lncRNA, peptides, and synthetic drugs. However, systemically delivered exosomes accumulate in liver, kidney, and spleen. Targeted exosomes can be obtained by displaying targeting molecules, such as peptides or antibody fragments recognizing target antigens, on the outer surface of exosomes. Display of glycosylphosphatidylinositol (GPI)-anchored nanobodies on EVs is a novel technique that enables EV display of a variety of proteins including antibodies, reporter proteins, and signaling molecules. However, naturally secreted exosomes show limited pharmaceutical acceptability. Engineered exosome mimetics that incorporate desirable components of natural exosomes into synthetic liposomes or nanoparticles, and are assembled using controllable procedures may be more acceptable pharmaceutically. In this communication, we review the current understanding of physiological and pathophysiological roles of exosomes, their potential applications as diagnostic markers, and current efforts to develop improved exosome-based drug delivery systems.
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- 2017
14. Supporting data on in vitro cardioprotective and proliferative paracrine effects by the human amniotic fluid stem cell secretome
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Carolina Balbi, Francesco Santini, Sveva Bollini, Agnese Palmeri, Vittorio Rosti, Tessa van Herwaarden, Mauro Giacca, Francesca Campagnoli, Lucio Barile, Marie-José Goumans, Ambra Costa, Silvia Moimas, Pierangela De Biasio, Kirsten Lodder, Anke M. Smits, Francesco Moccia, University of Zurich, Balbi, Carolina, Lodder, Kirsten, Costa, Ambra, Moimas, Silvia, Moccia, Francesco, van Herwaarden, Tessa, Rosti, Vittorio, Campagnoli, Francesca, Palmeri, Agnese, De Biasio, Pierangela, Santini, Francesco, Giacca, Mauro, Goumans, Marie-Josè, Barile, Lucio, Smits, Anke M, and Bollini, Sveva
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Chemokine ,Endothelial progenitors ,Amniotic fluid ,Angiogenesis ,medicine.medical_treatment ,Proliferation ,Paracrine effect ,610 Medicine & health ,Cardioprotection ,Biology ,lcsh:Computer applications to medicine. Medical informatics ,Regenerative medicine ,11171 Cardiocentro Ticino ,Neonatal cardiomyocyte ,03 medical and health sciences ,Paracrine signalling ,Cardiac progenitor cell ,0302 clinical medicine ,Biochemistry, Genetics and Molecular Biology ,Cardiac progenitor cells ,medicine ,Progenitor cell ,lcsh:Science (General) ,030304 developmental biology ,Endothelial progenitor ,0303 health sciences ,Multidisciplinary ,Cell biology ,Neonatal cardiomyocytes ,Angiogenesi ,Cytokine ,Human amniotic fluid stem cells ,Human amniotic fluid stem cell ,biology.protein ,lcsh:R858-859.7 ,Stem cell ,030217 neurology & neurosurgery ,lcsh:Q1-390 - Abstract
The data and information presented here refer to the research article entitled: “Reactivating endogenous mechanisms of cardiac regeneration via paracrine boosting with the human amniotic fluid stem cell secretome” (Balbi et al., 2019, Apr 04). This dataset illustrates the in vitro paracrine effect exerted by the human amniotic fluid stem cell secretome on rodent neonatal cardiomyocytes, human endothelial progenitors and different subsets of cardiac progenitor cells. Cytokine/chemokine profiling of the human amniotic fluid stem cell secretome is provided as well. This data can provide useful insights in regenerative medicine as demonstrating the in vitro cardioprotective and proliferative secretory paracrine potential of human fetal stem cells. Keywords: Paracrine effect, Human amniotic fluid stem cells, Cardiac progenitor cells, Neonatal cardiomyocytes, Endothelial progenitors, Proliferation, Cardioprotection, Angiogenesis
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- 2019
15. Flow Cytometric Analysis of Extracellular Vesicles from Cell-conditioned Media
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Sara Bolis, Lucio Barile, Carolina Balbi, Giuseppe Vassalli, and University of Zurich
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0301 basic medicine ,General Chemical Engineering ,Sonication ,610 Medicine & health ,030204 cardiovascular system & hematology ,Conjugated system ,11171 Cardiocentro Ticino ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,03 medical and health sciences ,Extracellular Vesicles ,0302 clinical medicine ,1300 General Biochemistry, Genetics and Molecular Biology ,2400 General Immunology and Microbiology ,medicine ,Humans ,1500 General Chemical Engineering ,General Immunology and Microbiology ,Cluster of differentiation ,medicine.diagnostic_test ,CD63 ,General Neuroscience ,fungi ,2800 General Neuroscience ,food and beverages ,Flow Cytometry ,Microvesicles ,030104 developmental biology ,Membrane ,Culture Media, Conditioned ,Biophysics ,Ultracentrifuge - Abstract
Flow cytometry (FC) is the method of choice for semi-quantitative measurement of cell-surface antigen markers. Recently, this technique has been used for phenotypic analyses of extracellular vesicles (EV) including exosomes (Exo) in the peripheral blood and other body fluids. The small size of EV mandates the use of dedicated instruments having a detection threshold around 50-100 nm. Alternatively, EV can be bound to latex microbeads that can be detected by FC. Microbeads, conjugated with antibodies that recognize EV-associated markers/Cluster of Differentiation CD63, CD9, and CD81 can be used for EV capture. Exo isolated from CM can be analyzed with or without pre-enrichment by ultracentrifugation. This approach is suitable for EV analyses using conventional FC instruments. Our results demonstrate a linear correlation between Mean Fluorescence Intensity (MFI) values and EV concentration. Disrupting EV through sonication dramatically decreased MFI, indicating that the method does not detect membrane debris. We report an accurate and reliable method for the analysis of EV surface antigens, which can be easily implemented in any laboratory.
- Published
- 2019
16. Reactivating endogenous mechanisms of cardiac regeneration via paracrine boosting using the human amniotic fluid stem cell secretome
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Francesca Campagnoli, Pierangela De Biasio, Agnese Palmeri, Marie-José Goumans, Vittorio Rosti, Ambra Costa, Silvia Moimas, Tessa van Herwaarden, Anke M. Smits, Francesco Santini, Sveva Bollini, Lucio Barile, Kirsten Lodder, Mauro Giacca, Carolina Balbi, Francesco Moccia, University of Zurich, Bollini, Sveva, Balbi, C., Lodder, K., Costa, A., Moimas, S., Moccia, F., van Herwaarden, T., Rosti, V., Campagnoli, F., Palmeri, A., De Biasio, P., Santini, F., Giacca, M., Goumans, M. -J., Barile, L., Smits, A. M., and Bollini, S.
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Cardiac function curve ,Amniotic fluid ,heart regeneration ,Angiogenesis ,Cellular differentiation ,Endogeny ,610 Medicine & health ,030204 cardiovascular system & hematology ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,03 medical and health sciences ,Paracrine signalling ,Mice ,0302 clinical medicine ,stem cells ,Paracrine Communication ,Medicine ,Myocyte ,Animals ,Humans ,Myocytes, Cardiac ,030212 general & internal medicine ,Cells, Cultured ,Heart Failure ,Microscopy, Confocal ,business.industry ,amniotic fluid ,Cell Differentiation ,Cell biology ,Rats ,cardio protection ,stem cell ,Mice, Inbred C57BL ,Disease Models, Animal ,Animals, Newborn ,Culture Media, Conditioned ,Stem cell ,business ,Cardiology and Cardiovascular Medicine ,Stem Cell Transplantation - Abstract
Background: The adult mammalian heart retains residual regenerative capability via endogenous cardiac progenitor cell (CPC) activation and cardiomyocyte proliferation. We previously reported the paracrine cardioprotective capacity of human amniotic fluid-derived stem cells (hAFS) following ischemia or cardiotoxicity. Here we analyse the potential of hAFS secretome fractions for cardiac regeneration and future clinical translation.Methods: hAFS were isolated from amniotic fluid leftover samples from prenatal screening. hAFS conditioned medium (hAFS-CM) was obtained following hypoxic preconditioning. Anti-apoptotic, angiogenic and proliferative effects were evaluated on rodent neonatal cardiomyocytes (r/mNVCM), human endothelial colony forming cells (hECFC) and human CPC. Mice undergoing myocardial infarction (MI) were treated with hAFS-CM, hAFS-extracellular vesicles (hAFS-EV), or EV-depleted hAFS-CM(hAFS-DM) by single intra-myocardial administration and evaluated in the short and long term.Results: hAFS-CM improved mNVCM survival under oxidative and hypoxic damage, induced Ca2+-dependent angiogenesis in hECFC and triggered hCPC and rNVCM proliferation. hAFS-CM treatment after MI counteracted scarring, supported cardiac function, angiogenesis and cardiomyocyte cell cycle progression in the long term. hAFS-DM had no effect. hAFS-CM and hAFS-EV equally induced epicardium WT1+CPC reactivation. Although no CPC cardiovascular differentiation was observed, our data suggests contribution to local angiogenesis by paracrine modulation. hAFS-EV alone were able to recapitulate all the beneficial effects exerted by hAFS-CM, except for stimulation of vessel formation.Conclusions: hAFS-CM and hAFS-EV can improve cardiac repair and trigger cardiac regeneration via paracrine modulation of endogenous mechanisms. While both formulations are effective in sustaining myocardial renewal, hAFS-CM retains higher pro-angiogenic potential, while hAFS-EV particularly enhances cardiac function. (c) 2019 Elsevier B.V. All rights reserved.
- Published
- 2019
17. Circulating blood cells and extracellular vesicles in acute cardioprotection
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John Pernow, Claudia Penna, Péter Ferdinandy, Klaus T. Preissner, Lucio Barile, Michael V. Cohen, Henrique Girão, Ioanna Andreadou, James M. Downey, Pasquale Pagliaro, Hector A. Cabrera-Fuentes, Sean M. Davidson, Yochai Birnbaum, and University of Zurich
- Subjects
0301 basic medicine ,Blood Platelets ,Heart Injury ,Erythrocytes ,Haematopoietic cells ,Physiology ,Ischemia ,Myocardial Reperfusion Injury ,610 Medicine & health ,Cardioprotection ,030204 cardiovascular system & hematology ,Pharmacology ,Exosomes ,Ischaemia ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,03 medical and health sciences ,Extracellular Vesicles ,0302 clinical medicine ,Reperfusion therapy ,2737 Physiology (medical) ,Physiology (medical) ,medicine ,media_common.cataloged_instance ,Animals ,Humans ,Myocardial infarction ,Circulating MicroRNA ,European union ,Hemostatic function ,media_common ,Hemostasis ,business.industry ,Myocardium ,1314 Physiology ,medicine.disease ,Microvesicles ,3. Good health ,Invited Spotlight Reviews ,030104 developmental biology ,Reperfusion ,ST Elevation Myocardial Infarction ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,Signal Transduction - Abstract
During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
- Published
- 2019
18. Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration
- Author
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Giuseppe Vassalli, Giovanni G. Camici, Sara Bolis, Elisabetta Cervio, Giuseppina Milano, Vanessa Biemmi, A. Ciullo, Tiziano Moccetti, Emanuel T. Fertig, Lucio Barile, Mihaela Gherghiceanu, University of Zurich, and Barile, Lucio
- Subjects
0301 basic medicine ,Male ,Benzylamines ,Myocardial Infarction ,1607 Spectroscopy ,Fluorescent Antibody Technique ,Pharmacology ,Cyclams ,Cell therapy ,lcsh:Chemistry ,0302 clinical medicine ,Heterocyclic Compounds ,intravenous injection ,Myocardial infarction ,lcsh:QH301-705.5 ,Spectroscopy ,Cells, Cultured ,Ejection fraction ,General Medicine ,Flow Cytometry ,3. Good health ,Computer Science Applications ,030220 oncology & carcinogenesis ,10209 Clinic for Cardiology ,Systemic administration ,1606 Physical and Theoretical Chemistry ,Cardiac function curve ,Receptors, CXCR4 ,1503 Catalysis ,Cell Survival ,Blotting, Western ,Ischemia ,cardiac progenitor cells ,610 Medicine & health ,Enzyme-Linked Immunosorbent Assay ,macromolecular substances ,exosomes ,11171 Cardiocentro Ticino ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Animals ,Cell Survival/drug effects ,Cell Survival/genetics ,Cell Survival/physiology ,Chemokine CXCL12/genetics ,Chemokine CXCL12/metabolism ,Cryoelectron Microscopy ,Exosomes/metabolism ,Heterocyclic Compounds/therapeutic use ,Humans ,Myocardial Infarction/genetics ,Myocardial Infarction/metabolism ,Myocardial Infarction/therapy ,RNA, Messenger/genetics ,RNA, Messenger/metabolism ,Rats ,Rats, Wistar ,Receptors, CXCR4/antagonists & inhibitors ,Receptors, CXCR4/genetics ,Receptors, CXCR4/metabolism ,CXCR4 ,1312 Molecular Biology ,1706 Computer Science Applications ,medicine ,RNA, Messenger ,Physical and Theoretical Chemistry ,Progenitor cell ,Molecular Biology ,1604 Inorganic Chemistry ,business.industry ,Organic Chemistry ,fungi ,medicine.disease ,Chemokine CXCL12 ,carbohydrates (lipids) ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,business ,Reperfusion injury ,1605 Organic Chemistry - Abstract
Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of ExoCXCR4 significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to ExoCTRL (p <, 0.01). Hemodynamic measurements showed that ExoCXCR4 improved dp/dt min, as compared to ExoCTRL and PBS group. In vitro, ExoCXCR4 was more bioactive than ExoCTRL in preventing CM death. This in vitro effect was independent from SDF-1α, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease.
- Published
- 2019
19. Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity
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Giuseppe Vassalli, Sara Bolis, Dario Di Silvestre, Edoardo Lazzarini, Carolina Balbi, Vanessa Biemmi, Pierluigi Mauri, Lucio Barile, Pietro Ameri, Giuseppina Milano, A. Ciullo, and University of Zurich
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0301 basic medicine ,Male ,Physiology ,Nitric Oxide Synthase Type II ,030204 cardiovascular system & hematology ,Pharmacology ,Exosomes ,Ventricular Function, Left ,11459 Center for Molecular Cardiology ,Rats, Sprague-Dawley ,Ventricular Dysfunction, Left ,2737 Physiology (medical) ,0302 clinical medicine ,Cells, Cultured ,Ventricular Remodeling ,Chemistry ,Middle Aged ,3. Good health ,Systemic administration ,Administration, Intravenous ,Female ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,Cardiomyopathies ,medicine.drug ,Signal Transduction ,610 Medicine & health ,macromolecular substances ,Mesenchymal Stem Cell Transplantation ,Exosome ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,03 medical and health sciences ,In vivo ,Physiology (medical) ,medicine ,Animals ,Humans ,Doxorubicin ,Progenitor cell ,Rats, Wistar ,Aged ,Cardiotoxicity ,Myocardium ,Mesenchymal stem cell ,technology, industry, and agriculture ,1314 Physiology ,Trastuzumab ,Fibrosis ,Microvesicles ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Animals, Newborn ,Reactive Oxygen Species - Abstract
AIMS Combined administration of anthracyclines (e.g. doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2), is an effective treatment for HER2-positive breast cancer. However, both agents are associated with cardiac toxicity. Human cardiac-resident mesenchymal progenitor cells (CPCs) secrete extracellular vesicles including nanosized exosomes which protect against myocardial ischaemia. Here, we investigated the effects of these exosomes using a novel model of Dox/Trz-mediated cardiotoxicity. METHODS AND RESULTS CPCs were derived from cardiac atrial appendage specimens from patients who underwent heart surgery for heart valve disease and/or ischaemic heart disease, and exosomes were purified from CPC conditioned media. Proteomics analyses revealed that CPC exosomes contained multiple proteins involved in redox processes. Dox/Trz induced a significant increase in reactive oxygen species (ROS) in rat cardiomyocytes, which was prevented by CPC exosomes. In vivo, rats received six doses of Dox (Days 1-11), followed by six doses of Trz (Days 19-28). Three doses of either exosomes or exosome suspension vehicle were injected intravenously on Days 5, 11, and 19 in the treatment and control groups, respectively. Dox/Trz induced myocardial fibrosis, CD68+ inflammatory cell infiltrates, inducible nitric oxide synthase expression, and left ventricular dysfunction. CPC exosomes prevented these effects. These vesicles were highly enriched in miR-146a-5p compared with human dermal fibroblast exosomes. Dox upregulated Traf6 and Mpo, two known miR-146a-5p target genes (which encode signalling mediators of inflammatory and cell death axes) in myocytes. CPC exosomes suppressed miR-146a-5p target genes Traf6, Smad4, Irak1, Nox4, and Mpo in Dox-treated cells. Specific silencing of miR-146a-5p abrogated exosome-mediated suppression of those genes leading to an increase in Dox-induced cell death. CONCLUSIONS Human CPC exosomes attenuate Dox-/Trz-induced oxidative stress in cardiomyocytes. Systemic administration of these vesicles prevents Dox/Trz cardiotoxicity in vivo. miR-146a-5p mediates some of the benefits of exosomes in this setting.
- Published
- 2018
20. Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease
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Alessio Burrello, Jacopo Burrello, Dario Di Silvestre, Cinthia Farina, Sara Bolis, Alain Kaelin-Lang, Elena Vacchi, Giorgia Melli, Lucio Barile, G. Vassalli, Pierluigi Mauri, Carlo W. Cereda, and University of Zurich
- Subjects
Male ,Pathology ,medicine.medical_specialty ,610 Medicine & health ,medicine.disease_cause ,Sensitivity and Specificity ,11171 Cardiocentro Ticino ,Article ,Flow cytometry ,Extracellular Vesicles ,Atrophy ,Immune system ,Parkinsonian Disorders ,medicine ,Humans ,Multiplex ,Protein Interaction Maps ,Aged ,Aged, 80 and over ,Receiver operating characteristic ,medicine.diagnostic_test ,business.industry ,Area under the curve ,Parkinson Disease ,Extracellular vesicle ,Middle Aged ,Multiple System Atrophy ,Immune dysregulation ,Flow Cytometry ,medicine.disease ,2728 Neurology (clinical) ,Cross-Sectional Studies ,Tauopathies ,Neurology ,2808 Neurology ,Case-Control Studies ,Antigens, Surface ,Female ,Supervised Machine Learning ,Neurology (clinical) ,business ,Biomarkers - Abstract
ObjectiveTo develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform.MethodsPlasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort.ResultsDistinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations.ConclusionsImmune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP.
- Published
- 2020
21. Exosomes From Human Cardiac Progenitor Cells for Therapeutic Applications: Development of a GMP-Grade Manufacturing Method
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Gabriella Andriolo, Elena Provasi, Viviana Lo Cicero, Andrea Brambilla, Sabrina Soncin, Tiziano Torre, Giuseppina Milano, Vanessa Biemmi, Giuseppe Vassalli, Lucia Turchetto, Lucio Barile, Marina Radrizzani, University of Zurich, and Andriolo, Gabriella
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0301 basic medicine ,Physiology ,CD34 ,cardiac progenitor cells ,610 Medicine & health ,macromolecular substances ,exosomes ,030204 cardiovascular system & hematology ,Exosome ,11171 Cardiocentro Ticino ,lcsh:Physiology ,03 medical and health sciences ,0302 clinical medicine ,2737 Physiology (medical) ,In vivo ,Physiology (medical) ,Methods ,Medicine ,good manufacturing practices ,large-scale production ,quality control ,CD90 ,Progenitor cell ,lcsh:QP1-981 ,business.industry ,Mesenchymal stem cell ,1314 Physiology ,Microvesicles ,Cell biology ,030104 developmental biology ,Cell culture ,business - Abstract
Exosomes, nanosized membrane vesicles secreted by cardiac progenitor cells (Exo-CPC), inhibit cardiomyocyte apoptosis under stress conditions, promote angiogenesis in vitro , and prevent the early decline in cardiac function after myocardial infarction in vivo in preclinical rat models. The recognition of exosome-mediated effects has moved attempts at developing cell-free approaches for cardiac repair. Such approaches offer major advantages including the fact that exosomes can be stored as ready-to-use agents and delivered to patients with acute coronary syndromes. The aim of the present work was the development of a good manufacturing practice (GMP)-grade method for the large-scale preparation of Exo-CPC as a medicinal product, for a future clinical translation. A GMP-compliant manufacturing method was set up, based on large-scale cell culture in xeno-free conditions, collection of up to 8 l of exosome-containing conditioned medium and isolation of Exo-CPC through tangential flow filtration. Quality control tests were developed and carried out to evaluate safety, identity, and potency of both cardiac progenitor cells (CPC) as cell source and Exo-CPC as final product (GMP-Exo-CPC). CPC, cultured in xeno-free conditions, showed a lower doubling-time than observed in research-grade condition, while producing exosomes with similar features. Cells showed the typical phenotype of mesenchymal progenitor cells (CD73/CD90/CD105 positive, CD14/CD20/CD34/CD45/HLA-DR negative), and expressed mesodermal (TBX5/TBX18) and cardiac-specific (GATA4/MESP1) transcription factors. Purified GMP-Exo-CPC showed the typical nanoparticle tracking analysis profile and expressed main exosome markers (CD9/CD63/CD81/TSG101). The GMP manufacturing method guaranteed high exosome yield (>10 13 particles) and consistent removal (≥97%) of contaminating proteins. The resulting GMP-Exo-CPC were tested for safety, purity, identity, and potency in vitro , showing functional anti-apoptotic and pro-angiogenic activity. The therapeutic efficacy was validated in vivo in rats, where GMP-Exo-CPC ameliorated heart function after myocardial infarction. Our standardized production method and testing strategy for large-scale manufacturing of GMP-Exo-CPC open new perspectives for reliable human therapeutic applications for acute myocardial infarction syndrome and can be easily applied to other cell sources for different therapeutic areas.
- Published
- 2018
22. Notch pathway activation enhances cardiosphere in vitro expansion
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Consuelo Torrini, Chiara Collesi, Giuseppe Vassalli, Ilaria Secco, Mauro Giacca, Lorena Zentilin, Lucio Barile, Secco, Ilaria, Barile, Lucio, Torrini, Consuelo, Zentilin, Lorena, Vassalli, Giuseppe, Giacca, Mauro, Collesi, Chiara, and University of Zurich
- Subjects
0301 basic medicine ,Toxicology screening ,Cardiac Progenitors ,Notch ,Genetic Vectors ,Adeno-associated virus (AAV) ,Notch signaling pathway ,Regulator ,610 Medicine & health ,030204 cardiovascular system & hematology ,Biology ,Transfection ,11171 Cardiocentro Ticino ,Virus ,1307 Cell Biology ,03 medical and health sciences ,0302 clinical medicine ,Micro-RNA ,Adeno‐associated virus (AAV) ,Gene expression ,microRNA ,Humans ,Myocytes, Cardiac ,Receptor, Notch1 ,Cells, Cultured ,Cell Proliferation ,Micro‐RNAs ,Poorly differentiated ,Calcium-Binding Proteins ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Micro-RNAs ,Cell Biology ,Original Articles ,Dependovirus ,In vitro ,Cell biology ,MicroRNAs ,030104 developmental biology ,1313 Molecular Medicine ,Molecular Medicine ,Original Article ,Jagged-1 Protein ,Signal Transduction - Abstract
Cardiospheres (CSps) are self‐assembling clusters of a heterogeneous population of poorly differentiated cells outgrowing from in vitro cultured cardiac explants. Scanty information is available on the molecular pathways regulating CSp growth and their differentiation potential towards cardiac and vascular lineages. Here we report that Notch1 stimulates a massive increase in both CSp number and size, inducing a peculiar gene expression programme leading to a cardiovascular molecular signature. These effects were further enhanced using Adeno‐Associated Virus (AAV)‐based gene transfer of activated Notch1‐intracellular domain (N1‐ICD) or soluble‐Jagged1 (sJ1) ligand to CSp‐forming cells. A peculiar effect was exploited by selected pro‐proliferating miRNAs: hsa‐miR‐590‐3p induced a cardiovascular gene expression programme, while hsa‐miR‐199a‐3p acted as the most potent stimulus for the activation of the Notch pathway, thus showing that, unlike in adult cardiomyocytes, these miRNAs involve Notch signalling activation in CSps. Our results identify Notch1 as a crucial regulator of CSp growth and differentiation along the vascular lineage, raising the attracting possibility that forced activation of this pathway might be exploited to promote in vitro CSp expansion as a tool for toxicology screening and cell‐free therapeutic strategies.
- Published
- 2018
23. Angiogenic activity of exosomes isolated from human pericardial fluid
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Giuseppe Vassalli, Lucio Barile, and University of Zurich
- Subjects
Economics and Econometrics ,Budding ,Endosome ,Chemistry ,Cell ,Pericardial fluid ,Forestry ,Endogeny ,610 Medicine & health ,Compartment (chemistry) ,Microvesicles ,11171 Cardiocentro Ticino ,Cell biology ,Surface membrane ,medicine.anatomical_structure ,Materials Chemistry ,Media Technology ,medicine - Abstract
Exosomes are endogenous, nanosized extracellular vesicles secreted by cells. Unlike microvesicles, which are released by direct budding from the surface membrane, exosomes originate in the endosomal compartment of a parent cell (1).
- Published
- 2017
24. First Characterization of Human Amniotic Fluid Stem Cell Extracellular Vesicles as a Powerful Paracrine Tool Endowed with Regenerative Potential
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Martina Piccoli, Andrea Armirotti, Ranieri Cancedda, Daniele Reverberi, Massimo Mogni, Andrea Papait, Pamela Becherini, Michela Pozzobon, Luisa Pascucci, Tiziano Bandiera, Lucio Barile, Carolina Balbi, Elisa Principi, Domenico A. Coviello, Sveva Bollini, Luigi Varesio, University of Zurich, and Bollini, Sveva
- Subjects
Male ,0301 basic medicine ,Proliferation ,Apoptosis ,Inbred C57BL ,Exosomes ,Regenerative medicine ,1309 Developmental Biology ,1307 Cell Biology ,Mice ,Fetal stem cells ,Translational Research Articles and Reviews ,Extracellular vesicles ,MiRNA ,Paracrine communication ,Tissue regeneration ,Developmental Biology ,Cell Biology ,Settore BIO/13 - BIOLOGIA APPLICATA ,Fetal Stem Cells ,miRNA ,Stem Cells ,Cell Differentiation ,Skeletal ,General Medicine ,Cell biology ,Muscular Atrophy ,medicine.anatomical_structure ,Muscle ,Stem cell ,Paracrine Communication ,610 Medicine & health ,Fetal and Neonatal Stem Cells ,Biology ,11171 Cardiocentro Ticino ,03 medical and health sciences ,Paracrine signalling ,medicine ,Animals ,Humans ,Muscle, Skeletal ,Cell Proliferation ,Skeletal muscle ,Amniotic Fluid ,Microvesicles ,Mice, Inbred C57BL ,Transplantation ,MicroRNAs ,030104 developmental biology ,Stem Cell Transplantation - Abstract
Human amniotic fluid stem cells (hAFS) have shown a distinct secretory profile and significant regenerative potential in several preclinical models of disease. Nevertheless, little is known about the detailed characterization of their secretome. Herein we show for the first time that hAFS actively release extracellular vesicles (EV) endowed with significant paracrine potential and regenerative effect. c-KIT+ hAFS were isolated from leftover samples of amniotic fluid from prenatal screening and stimulated to enhance EV release (24 hours 20% O2 versus 1% O2 preconditioning). The capacity of the c-KIT+ hAFS-derived EV (hAFS-EV) to induce proliferation, survival, immunomodulation, and angiogenesis were investigated in vitro and in vivo. The hAFS-EV regenerative potential was also assessed in a model of skeletal muscle atrophy (HSA-Cre, SmnF7/F7 mice), in which mouse AFS transplantation was previously shown to enhance muscle strength and survival. hAFS secreted EV ranged from 50 up to 1,000 nm in size. In vitro analysis defined their role as biological mediators of regenerative, paracrine effects while their modulatory role in decreasing skeletal muscle inflammation in vivo was shown for the first time. Hypoxic preconditioning significantly induced the enrichment of exosomes endowed with regenerative microRNAs within the hAFS-EV. In conclusion, this is the first study showing that c-KIT+ hAFS dynamically release EV endowed with remarkable paracrine potential, thus representing an appealing tool for future regenerative therapy.
- Published
- 2017
25. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction
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Francesco Siclari, Tiziano Moccetti, Elisabetta Cervio, Vincenzo Lionetti, Mihaela Gherghiceanu, Giuseppe Vassalli, Marco Matteucci, Lucio Barile, T. Torre, Laurentiu M. Popescu, University of Zurich, and Barile, Lucio
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Physiology ,Angiogenesis ,Myocardial Infarction ,Apoptosis ,610 Medicine & health ,Biology ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,Umbilical vein ,Mice ,Paracrine signalling ,2737 Physiology (medical) ,Physiology (medical) ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Secretion ,Rats, Wistar ,Fibroblast ,Cells, Cultured ,Tube formation ,Stem Cells ,Cell Differentiation ,1314 Physiology ,Microvesicles ,Cell biology ,MicroRNAs ,medicine.anatomical_structure ,Culture Media, Conditioned ,Extracellular Space ,Cardiology and Cardiovascular Medicine - Abstract
AIMS: Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS: CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION: EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.
- Published
- 2014
26. Exosomes for Intramyocardial Intercellular Communication
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Tiziano Moccetti, Lucio Barile, Giuseppe Vassalli, Elisabetta Cervio, University of Zurich, and Vassalli, Giuseppe
- Subjects
Cell type ,lcsh:Internal medicine ,Article Subject ,Angiogenesis ,610 Medicine & health ,Review Article ,030204 cardiovascular system & hematology ,Bioinformatics ,11171 Cardiocentro Ticino ,1307 Cell Biology ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,microRNA ,1312 Molecular Biology ,Medicine ,lcsh:RC31-1245 ,Molecular Biology ,health care economics and organizations ,030304 developmental biology ,0303 health sciences ,business.industry ,Cell Biology ,Microvesicles ,3. Good health ,Cell biology ,Apoptosis ,business ,Homeostasis ,Intracellular - Abstract
Cross-talk between different cell types plays central roles both in cardiac homeostasis and in adaptive responses of the heart to stress. Cardiomyocytes (CMs) send biological messages to the other cell types present in the heart including endothelial cells (ECs) and fibroblasts. In turn, CMs receive messages from these cells. Recent evidence has now established that exosomes, nanosized secreted extracellular vesicles, are crucial mediators of such messages. CMs, ECs, cardiac fibroblasts, and cardiac progenitor cells (CPCs) release exosomes carrying nonrandom subsets of proteins, lipids, and nucleic acids present in their cells of origin. Exosomes secreted from CMs are internalized by fibroblasts and regulate gene expression in these cells as well as in ECs. CPC-derived exosomes protect CMs against apoptosis while also stimulating angiogenesis. They are rich in cardioprotective and proangiogenic microRNAs such as miR-146, miR-210, and miR-132. When injected into infracted heartsin vivo, CPC-derived exosomes reduce infarct size and improve cardiac function. Thus, exosomes are emerging both as key mediators of intercellular communication in the heart and as therapeutic candidates for heart disease.
- Published
- 2015
27. Erratum to: Highlights from the 2014 Lugano Stem Cell Meeting
- Author
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Annarosa Leri, Daniel Sürder, Sabrina Soncin, Tiziano Moccetti, Lucio Barile, Marina Radrizzani, Piero Anversa, Lucia Turchetto, Elisabetta Cervio, Tiziano Tallone, Viviana Lo Cicero, Sara Bolis, Marco Moccetti, Gabriella Andriolo, Giuseppe Vassalli, Silvana Bardelli, University of Zurich, and Bardelli, Silvana
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Philosophy ,Pharmaceutical Science ,610 Medicine & health ,11171 Cardiocentro Ticino ,2604 Applied Mathematics ,Genetics ,1706 Computer Science Applications ,Molecular Medicine ,2613 Statistics and Probability ,Cardiology and Cardiovascular Medicine ,Title page ,Genetics (clinical) ,Classics ,Cicero - Abstract
Erratum to: J. of Cardiovasc. Trans. Res. DOI 10.1007/s12265-014-9601-5. Please note that "Lo Cicero" is the surname of coauthor Viviana Lo Cicero, not "Cicero", as the rendering of this coauthor’s surname at the foot of the title page of the article as published would lead readers to believe.
- Published
- 2015
28. Combination of miRNA499 and miRNA133 exerts a synergic effect on cardiac differentiation
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Manuela Mura, Maria Chiara Ciuffreda, Antonio Zaza, Claudia Altomare, Patrizia Danieli, Gianluca Viarengo, Federica Pisano, Marcella Rocchetti, Massimiliano Gnecchi, Elisabetta Cervio, Giuseppe Malpasso, Lucio Barile, Francesco Copes, University of Zurich, Gnecchi, Massimiliano, Pisano, F, Altomare, C, Cervio, E, Barile, L, Rocchetti, M, Ciuffreda, M, Malpasso, G, Copes, F, Mura, M, Danieli, P, Viarengo, G, Zaza, A, and Gnecchi, M
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Organogenesis ,P19 cell ,Cellular differentiation ,610 Medicine & health ,Stem cells ,Biology ,Regenerative Medicine ,11171 Cardiocentro Ticino ,Cell Line ,1309 Developmental Biology ,1307 Cell Biology ,Mice ,Animals ,Humans ,Myocytes, Cardiac ,Progenitor cell ,Cells, Cultured ,Stem cell ,Ryanodine receptor ,Mesenchymal stem cell ,Cell Differentiation ,MicroRNA ,Cardiac differentiation ,Cell Biology ,Molecular biology ,Cell biology ,P19 cells ,Electrophysiology ,MicroRNAs ,Cell culture ,1313 Molecular Medicine ,Molecular Medicine ,Developmental biology ,Developmental Biology - Abstract
Several studies have demonstrated that miRNA are involved in cardiac development, stem cell maintenance, and differentiation. In particular, it has been shown that miRNA133, miRNA1, and miRNA499 are involved in progenitor cell differentiation into cardiomyocytes. However, it is unknown whether different miRNA may act synergistically to improve cardiac differentiation. We used mouse P19 cells as a cardiogenic differentiation model. miRNA499, miRNA1, or miRNA133 were transiently over-expressed in P19 cells individually or in different combinations. The over-expression of miRNA499 alone increased the number of beating cells and the association of miRNA499 with miRNA133 exerted a synergistic effect, further increasing the number of beating cells. Real-time polymerase chain reaction showed that the combination of miRNA499 + 133 enhanced the expression of cardiac genes compared with controls. Western blot and immunocytochemistry for connexin43 and cardiac troponin T confirmed these findings. Importantly, caffeine responsiveness, a clear functional parameter of cardiac differentiation, was increased by miRNA499 in association with miRNA133 and was directly correlated with the activation of the cardiac troponin I isoform promoter. Cyclic contractions were reversibly abolished by extracellular calcium depletion, nifedipine, ryanodine, and IP3R blockade. Finally, we demonstrated that the use of miRNA499 + 133 induced cardiac differentiation even in the absence of dimethyl sulfoxide. Our results show that the areas spontaneously contracting possess electrophysiological and pharmacological characteristics compatible with true cardiac excitation-contraction coupling. The translational relevance of our findings was reinforced by the demonstration that the over-expression of miRNA499 and miRNA133 was also able to induce the differentiation of human mesenchymal stromal cells toward the cardiac lineage. Stem Cells 2015;33:1187–1199
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- 2015
29. Highlights from the 2014 Lugano Stem Cell Meeting
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Tiziano Tallone, Sara Bolis, Tiziano Moccetti, Marina Radrizzani, Marco Moccetti, Gabriella Andriolo, Lucia Turchetto, Elisabetta Cervio, Giuseppe Vassalli, Silvana Bardelli, Annarosa Leri, Daniel Sürder, Viviana Lo Cicero, Sabrina Soncin, Lucio Barile, Piero Anversa, University of Zurich, and Bardelli, Silvana
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2716 Genetics (clinical) ,3003 Pharmaceutical Science ,Pharmaceutical Science ,610 Medicine & health ,Biology ,Human genetics ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,1311 Genetics ,1313 Molecular Medicine ,Genetics ,Cancer research ,Molecular Medicine ,Stem cell ,Cardiology and Cardiovascular Medicine ,Genetics (clinical) - Published
- 2014
30. Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension
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Antonio Zaza, Carlotta Ronchi, Luca Sala, Lidia Staszewsky, Jacopo Lucchetti, Claudia Altomare, Vanessa Zambelli, Roberto Latini, Riccardo Rizzetto, Marcella Rocchetti, Ilaria Russo, Marco Gobbi, Laura Cornaghi, Matteo Alemanni, Lucio Barile, Gaspare Mostacciuolo, Rocchetti, M, Sala, L, Rizzetto, R, Staszewsky, L, Alemanni, M, Zambelli, V, Russo, I, Barile, L, Cornaghi, L, Altomare, C, Ronchi, C, Mostacciuolo, G, Lucchetti, J, Gobbi, M, Latini, R, Zaza, A, University of Zurich, and Zaza, Antonio
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Male ,Time Factors ,Physiology ,Piperazines ,Sodium Channels ,Muscle hypertrophy ,Membrane Potentials ,Rats, Sprague-Dawley ,2737 Physiology (medical) ,Ranolazine ,Medicine ,Myocytes, Cardiac ,Monocrotaline ,Ventricular Remodeling ,medicine.anatomical_structure ,Ventricular pressure ,Cardiology ,Collagen ,Cardiology and Cardiovascular Medicine ,Sodium Channel Blockers ,medicine.medical_specialty ,Hypertension, Pulmonary ,Diastole ,610 Medicine & health ,Pulmonary Artery ,Vascular Remodeling ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,Pulmonary hypertension ,Right ventricular hypertrophy ,Arteriole ,medicine.artery ,Internal medicine ,Late sodium current ,Physiology (medical) ,Animals ,Calcium Signaling ,Hypertrophy, Right Ventricular ,Myosin Heavy Chains ,business.industry ,Sodium ,Remodelling ,1314 Physiology ,Hypertrophy ,medicine.disease ,Fibrosis ,Rats ,Disease Models, Animal ,Blood pressure ,Vascular resistance ,Ventricular Function, Right ,Acetanilides ,Vascular Resistance ,business - Abstract
Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current ( I NaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive I NaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available I NaL blocker, may prevent constitutive I NaL enhancement and PAH-induced myocardial remodelling. Methods and results PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. I NaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, I NaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented I NaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. Conclusion PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive I NaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.
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- 2014
31. Exosomes secreted by adult human cardiac progenitor cells inhibit cardiomyocyte apoptosis, stimulate angiogenesis, and improve cardiac function after myocardial infarction
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Elisabetta Cervio, L. M. Popescu, Giuseppe Vassalli, Vincenzo Lionetti, T. Torre, T. Moccetti, Lucio Barile, Marco Matteucci, Francesca Siclari, Mihaela Gherghiceanu, and University of Zurich
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Cardiac function curve ,Cancer Research ,Transplantation ,Cardiac progenitors ,business.industry ,Angiogenesis ,Immunology ,610 Medicine & health ,Cell Biology ,medicine.disease ,11171 Cardiocentro Ticino ,Microvesicles ,Oncology ,Cancer research ,Immunology and Allergy ,Medicine ,Myocardial infarction ,business ,Genetics (clinical) ,Cardiomyocyte apoptosis - Published
- 2014
32. Human Cardiospheres as a Source of Multipotent Stem and Progenitor Cells
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Laurenţiu M. Popescu, Giuseppe Vassalli, Lucio Barile, Tiziano Moccetti, Mihaela Gherghiceanu, University of Zurich, and Vassalli, Giuseppe
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Pathology ,medicine.medical_specialty ,Cell type ,lcsh:Internal medicine ,Stromal cell ,Article Subject ,Genetic enhancement ,Cell ,Connexin ,610 Medicine & health ,Review Article ,030204 cardiovascular system & hematology ,11171 Cardiocentro Ticino ,1307 Cell Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,1312 Molecular Biology ,Progenitor cell ,lcsh:RC31-1245 ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,business.industry ,Mesenchymal stem cell ,Cell Biology ,Cell biology ,medicine.anatomical_structure ,Stem cell ,business - Abstract
Cardiospheres (CSs) are self-assembling multicellular clusters from the cellular outgrowth from cardiac explants cultured in nonadhesive substrates. They contain a core of primitive, proliferating cells, and an outer layer of mesenchymal/stromal cells and differentiating cells that express cardiomyocyte proteins and connexin 43. Because CSs contain both primitive cells and committed progenitors for the three major cell types present in the heart, that is, cardiomyocytes, endothelial cells, and smooth muscle cells, and because they are derived from percutaneous endomyocardial biopsies, they represent an attractive cell source for cardiac regeneration. In preclinical studies, CS-derived cells (CDCs) delivered to infarcted hearts resulted in improved cardiac function. CDCs have been tested safely in an initial phase-1 clinical trial in patients after myocardial infarction. Whether or not CDCs are superior to purified populations, for example, c-kit+cardiac stem cells, or to gene therapy approaches for cardiac regeneration remains to be evaluated.
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- 2013
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33. Ultrastructural Evidence of Exosome Secretion by Progenitor Cells in Adult Mouse Myocardium and Adult Human Cardiospheres
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Giuseppe Vassalli, Tiziano Moccetti, Laurentiu M. Popescu, Lucio Barile, Mihaela Gherghiceanu, University of Zurich, and Vassalli, Giuseppe
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Pathology ,Health, Toxicology and Mutagenesis ,Myocardial Ischemia ,lcsh:Medicine ,Review Article ,030204 cardiovascular system & hematology ,Exosomes ,Cell therapy ,Mice ,0302 clinical medicine ,Cell-Derived Microparticles ,0303 health sciences ,Clinical Trials as Topic ,Stem Cells ,General Medicine ,Flow Cytometry ,Cell biology ,Endothelial stem cell ,1305 Biotechnology ,Molecular Medicine ,Stem cell ,Biotechnology ,medicine.medical_specialty ,Article Subject ,lcsh:Biotechnology ,Paracrine Communication ,610 Medicine & health ,Biology ,Exosome ,Transplantation, Autologous ,11171 Cardiocentro Ticino ,03 medical and health sciences ,Paracrine signalling ,1311 Genetics ,lcsh:TP248.13-248.65 ,Spheroids, Cellular ,2307 Health, Toxicology and Mutagenesis ,1312 Molecular Biology ,Genetics ,medicine ,Animals ,Humans ,Progenitor cell ,Molecular Biology ,030304 developmental biology ,Myocardium ,lcsh:R ,Embryonic stem cell ,1313 Molecular Medicine ,Stem Cell Transplantation - Abstract
The demonstration of beneficial effects of cell therapy despite the persistence of only few transplanted cellsin vivosuggests secreted factors may be the active component of this treatment. This so-called paracrine hypothesis is supported by observations that culture media conditioned by progenitor cells contain growth factors that mediate proangiogenic and cytoprotective effects. Cardiac progenitor cells in semi-suspension culture form spherical clusters (cardiospheres) that deliver paracrine signals to neighboring cells. A key component of paracrine secretion is exosomes, membrane vesicles that are stored intracellularly in endosomal compartments and are secreted when these structures fuse with the cell plasma membrane. Exosomes have been identified as the active component of proangiogenic effects of bone marrow CD34+stem cells in mice and the regenerative effects of embryonic mesenchymal stem cells in infarcted hearts in pigs and mice. Here, we provide electron microscopic evidence of exosome secretion by progenitor cells in mouse myocardium and human cardiospheres. Exosomes are emerging as an attractive vector of paracrine signals delivered by progenitor cells. They can be stored as an “off-the-shelf” product. As such, exosomes have the potential for circumventing many of the limitations of viable cells for therapeutic applications in regenerative medicine.
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- 2012
34. Roles of exosomes in cardioprotection
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Giuseppe Vassalli, Lucio Barile, Eduardo Marbán, Tiziano Moccetti, University of Zurich, and Vassalli, Giuseppe
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0301 basic medicine ,Endosome ,610 Medicine & health ,030204 cardiovascular system & hematology ,Exosomes ,11171 Cardiocentro Ticino ,2705 Cardiology and Cardiovascular Medicine ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,microRNA ,Humans ,Medicine ,Myocytes, Cardiac ,Progenitor cell ,Cardioprotection ,business.industry ,Stem Cells ,Endothelial Cells ,Microvesicles ,Cell biology ,030104 developmental biology ,Cardiovascular Diseases ,Ischemic Preconditioning, Myocardial ,Immunology ,Stem cell ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Myoblasts, Cardiac ,Intracellular - Abstract
Exosomes are extracellular vesicles of endosomal origin which have emerged as key mediators of intercellular communication. All major cardiac cell types-including cardiomyocytes, endothelial cells, and fibroblasts-release exosomes that modulate cellular functions. Exosomes released from human cardiac progenitor cells (CPCs) are cardioprotective and improve cardiac function after myocardial infarction to an extent comparable with that achieved by their parent cells. Cardiac progenitor cell-derived exosomes are enriched in cardioprotective microRNAs, particularly miR-146a-3p. Circulating exosomes mediate remote ischaemic preconditioning. Moreover, they currently are being investigated as diagnostic markers. The discovery that cell-derived extracellular signalling organelles mediate the paracrine effects of stem cells suggests that cell-free strategies could supplant cell transplantation. This review discusses emerging roles of exosomes in cardiovascular physiology, with a focus on cardioprotective activities of CPC-derived exosomes.
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- 2016
35. Exosomes secreted by human cardiac progenitors contain micro-RNA with cardioprotective and pro-angiogenic activities
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T. Moccetti, Lucio Barile, L. M. Popescu, Elisabetta Cervio, Vincenzo Lionetti, Marco Matteucci, T. Torre, Giuseppe Vassalli, Mihaela Gherghiceanu, Francesca Siclari, and University of Zurich
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Cancer Research ,medicine.medical_specialty ,Immunology ,Infarction ,610 Medicine & health ,11171 Cardiocentro Ticino ,Pharmacotherapy ,Internal medicine ,medicine ,Clinical endpoint ,Immunology and Allergy ,Genetics (clinical) ,Transplantation ,Ejection fraction ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,Cell Biology ,medicine.disease ,Oncology ,Bypass surgery ,Positron emission tomography ,Heart failure ,Cardiology ,business - Abstract
promising new method to treat heart failure but results from clinical trials have been mixed. Here, we present results from our study combining BMMC therapy with coronary bypass surgery (CABG). Materials and methods: First, we enrolled 107 ischemic heart failure patients scheduled for CABG. These patients went through a 4to 12week period with optimized drug therapy. If left ventricular ejection fraction (LVEF) remained 45%, a patient was eligible for the actual study. In a randomized, double-blind manner, the still eligible 39 patients received intramyocardial injections of BMMCs or vehicle intraoperatively into the infarction and border area during CABG. We measured global and segmental LV function and scar size by magnetic resonance imaging (MRI), and viability by positron emission tomography (PET) and singlephoton emission tomography (SPECT), preoperatively and after 1-year follow-up. Results: LVEF, the primary end point measure, improved by a median of 5.6% among controls (IQR 0.2 to 10.1) and by 4.8% in the BMMC patients (IQR -0.5 to 8.2) (P1⁄40.59). Wall thickening in injected segments rose by a median of 4.5% in the control group (IQR -18.1 to 23.9) and by 5.5% in the BMMC patients (IQR -6.6 to 26.5) (P1⁄40.68). Viability by PET and SPECT did not differ between the groups. Myocardial scar volume by MRI in injected segments rose by a median of 5.1% in the control group (IQR -3.3 to 10.8) but fell by 13.1% in the BMMC group (IQR -21.4 to -6.5) (P1⁄40.0002). Conclusions: As an adjunct to CABG, BMMC therapy failed to affect global or local LV systolic function or viability by PET and SPECT during 1-year follow-up. Interestingly, however, it affected one essential prognostic marker: myocardial scar size was significantly reduced by BMMC therapy. Long-term studies are necessary to elucidate this finding’s permanence.
- Published
- 2014
36. Epigenetic regulation of myocardial homeostasis, Self-regeneration and senescence
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Gaia Papini, Lucio Barile, Enrica Ciofini, Vincenzo Lionetti, Marco Matteucci, University of Zurich, and Lionetti, Vincenzo
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Senescence ,Epigenetic regulation of neurogenesis ,Clinical Biochemistry ,610 Medicine & health ,1308 Clinical Biochemistry ,Biology ,11171 Cardiocentro Ticino ,Epigenesis, Genetic ,Histones ,Paracrine signalling ,Drug Discovery ,microRNA ,myocardium ,Animals ,Humans ,Regeneration ,Myocytes, Cardiac ,Epigenetics ,Cellular Senescence ,Pharmacology ,3002 Drug Discovery ,Regeneration (biology) ,Acetylation ,DNA Methylation ,Cell biology ,Epigenetics, myocardium, regeneration ,3004 Pharmacology ,1313 Molecular Medicine ,Immunology ,DNA methylation ,Molecular Medicine ,Reprogramming - Abstract
The adult myocardium has limited capacity to preserve, renew or rejuvenate itself. The local microenvironment may induce epigenetic changes affecting the survival, proliferation, function and senescence of cardiac cells at rest and following the exposure to different stressors. The cellular response to microenvironment is characterized by the release of ions, oxygen free radicals, auto/paracrine factors and RNAs that drive the magnitude of gene reprogramming through the interaction with specific promoters. The epigenetic alterations may act at transcriptional and post-transcriptional level and change cardiac physiological traits. The abnormal DNA methylation underlies the progressive decay of contractile function and the angiogenic ability; while, the histone acetylation promotes the survival, function and proliferation of cardiac cells in the presence of ischemic microenvironment. At least, the expression and secretion of microRNAs and long noncoding RNAs may regulate the threshold to stress tolerance of adult cardiac cells and induce the matrix turnover as well. Natural or synthetic active compounds effectively modulate the epigenetic state of cardiac cells. Plant foods contain many active compounds with epigenetic properties and might assume a clinical significance as natural cardiac regenerators or rejuvenators. Our review describes novel epigenetic mechanisms that underpin myocardial remodeling, repair/ regeneration or senescence in order to support the development of most effective and reproducible rescue therapy of adult heart.
37. Altered functional differentiation of mesoangioblasts in a genetic myopathy
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Claudia Altomare, Stefania Crippa, Luca Sala, Lucio Barile, Antonio Zaza, Maurilio Sampaolesi, Marcella Rocchetti, Altomare, C, Barile, L, Rocchetti, M, Sala, L, Crippa, S, Sampaolesi, M, Zaza, A, University of Zurich, and Zaza, Antonio
- Subjects
medicine.medical_specialty ,Cell type ,mesoangioblast, stem cell, myopathy ,Action Potentials ,610 Medicine & health ,Biology ,11171 Cardiocentro Ticino ,1307 Cell Biology ,Mice ,Muscular Diseases ,Internal medicine ,Sarcoglycans ,medicine ,Animals ,Myocytes, Cardiac ,Progenitor cell ,Myopathy ,Muscle, Skeletal ,Cells, Cultured ,Mice, Knockout ,Mesoangioblast ,Stem Cells ,Skeletal muscle ,Heart ,Cell Biology ,Original Articles ,differentiation switch ,Phenotype ,β-sarcoglycan ,Cell biology ,Electrophysiology ,MicroRNAs ,Endocrinology ,medicine.anatomical_structure ,1313 Molecular Medicine ,Molecular Medicine ,cardiac mesoangioblasts ,Calcium ,medicine.symptom ,Stem cell ,C2C12 ,Muscle Contraction - Abstract
Mutations underlying genetic cardiomyopathies might affect differentiation commitment of resident progenitor cells. Cardiac mesoangioblasts (cMabs) are multipotent progenitor cells resident in the myocardium. A switch from cardiac to skeletal muscle differentiation has been recently described in cMabs from β-sarcoglycan-null mice (βSG(-/-) ), a murine model of genetic myopathy with early myocardial involvement. Although complementation with βSG gene was inconsequential, knock-in of miRNA669a (missing in βSG(-/-) cMabs) partially rescued the mutation-induced molecular phenotype. Here, we undertook a detailed evaluation of functional differentiation of βSG(-/-) cMabs and tested the effects of miRNA669a-induced rescue in vitro. To this end, cMabs were compared with neonatal cardiomyocytes (CMs) and skeletal muscle C2C12 cells, representative of cardiac and skeletal muscle respectively. Consistent with previous data on molecular patterns, electrophysiological and Ca(2+) -handling properties of βSG(-/-) cMabs were closer to C2C12 cells than to CM ones. Nevertheless, subtler aspects, including action potential contour, Ca(2+) -spark properties and RyR isoform expression, distinguished βSG(-/-) cMabs from C2C12 cells. Contrary to previous reports, wild-type cMabs failed to show functional differentiation towards either cell type. Knock-in of miRNA669a in βSG(-/-) cMabs rescued the wild-type functional phenotype, i.e. it completely prevented development of skeletal muscle functional responses. We conclude that miRNA669a expression, ablated by βSG deletion, may prevent functional differentiation of cMabs towards the skeletal muscle phenotype. ispartof: Journal of Cellular and Molecular Medicine vol:17 issue:3 pages:419-28 ispartof: location:England status: published
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