The Experts below are selected from a list of 20238 Experts worldwide ranked by ideXlab platform
Daniele Torella - One of the best experts on this subject based on the ideXlab platform.
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Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon?
'Hindawi Limited', 2019Co-Authors: Eleonora Cianflone, Marcello Rota, Cristina Chimenti, Michele Torella, Antonella De Angelis, Antonio P. Beltrami, Konrad Urbanek, Daniele TorellaAbstract:Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic Cellular and molecular changes in Cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of Cardiac aging have been the subject of intense study, the recent discovery that Cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous Cardiac Stem Cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of Cell turnover and renewal, has now been replaced by a dynamic model in which Cardiac Cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo Cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible Cell autonomous process. However, CSC aging could be a programmed Cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract Cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths
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the Cardiac Stem Cell compartment is indispensable for myocardial Cell homeostasis repair and regeneration in the adult
Stem Cell Research, 2014Co-Authors: Bernardo Nadalginard, Georgina M Ellison, Daniele TorellaAbstract:Abstract Resident Cardiac Stem Cells in embryonic, neonatal and adult mammalian heart have been identified by different membrane markers and transcription factors. However, despite a flurry of publications no consensus has been reached on the identity and actual regenerative effects of the adult Cardiac Stem Cells. Intensive research on the adult mammalian heart's capacity for self-renewal of its muscle Cell mass has led to a consensus that new cardiomyocytes (CMs) are indeed formed throughout adult mammalian life albeit at a disputed frequency. The physiological significance of this renewal, the origin of the new CMs, and the rate of adult CM turnover are still highly debated. Myocyte replacement, particularly after injury, was originally attributed to differentiation of a Stem Cell compartment. More recently, it has been reported that CMs are mainly replaced by the division of pre-existing post-mitotic CMs. These latter results, if confirmed, would shift the target of regenerative therapy toward boosting mature CM Cell-cycle re-entry. Despite this controversy, it is documented that the adult endogenous c-kitpos Cardiac Stem Cells (c-kitpos eCSCs) participate in adaptations to myocardial stress, and, when transplanted into the myocardium, regenerate most cardiomyocytes and microvasculature lost in an infarct. Nevertheless, the in situ myogenic potential of adult c-kitpos Cardiac Cells has been questioned. To revisit the regenerative potential of c-kitpos eCSCs, we have recently employed experimental protocols of severe diffuse myocardial damage in combination with several genetic murine models and Cell transplantation approaches showing that eCSCs are necessary and sufficient for CM regeneration, leading to complete Cellular, anatomical, and functional myocardial recovery. Here we will review the available data on adult eCSC biology and their regenerative potential placing it in the context of the different claimed mechanisms of CM replacement. These data are in agreement with and have reinforced our view that most CMs are replaced by de novo CM formation through the activation, myogenic commitment and specification of the eCSC cohort.
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the adult heart responds to increased workload with physiologic hypertrophy Cardiac Stem Cell activation and new myocyte formation
European Heart Journal, 2014Co-Authors: Cheryl D Waring, Daniele Torella, Andrew J Smith, Carla Vicinanza, Angela Papalamprou, Saranya Purushothaman, David F Goldspink, Bernardo NadalginardAbstract:Aims It is a dogma of cardiovascular pathophysiology that the increased Cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous Cardiac Stem/progenitor Cells (eCSCs) and new cardiomyocyte formation in physiological Cardiac remodelling remains unexplored. Methods and results In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (∼7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kitpos eCSCs increased their number and activated state in exercising vs. sedentary animals. c-kitpos eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5pos) or capillary (Ets-1pos) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-β1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kitpos eCSC proliferation and commitment in vitro , pointing to a similar role in vivo . Conclusion Intensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c-kitpos eCSCs. This leads to the generation of new myocardial Cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological Cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries).
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optimizing Cardiac repair and regeneration through activation of the endogenous Cardiac Stem Cell compartment
Journal of Cardiovascular Translational Research, 2012Co-Authors: Daniele Torella, Bernardo Nadalginard, Georgina M EllisonAbstract:Given the aging of the Western World and declining death rates due to acute coronary syndromes, the increasing trends in the magnitude and morbidity of heart failure (HF) are predicted to continue for the foreseeable future. It is imperative to develop effective therapies for the amelioration and prevention of HF. The search for the best Cell type to be used in clinical protocols of Cardiac regeneration is still on. That the adult mammalian heart harbors endogenous, multipotent Cardiac Stem/progenitor Cells (eCSCs) and that cardiomyocytes are replaced throughout adulthood represent a paradigm shift in cardiovascular biology. The presence of eCSCs supports the view that the heart can repair itself if the eCSCs can be properly stimulated. Pending a better understanding of eCSC biology, it should be possible to replace autologous Cell transplantation-based myocardial regeneration protocols with an “off-the-shelf,” readily available, and effective regenerative/reparative therapy based on activation of the eCSCs in situ.
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endogenous Cardiac Stem Cell activation by insulin like growth factor 1 hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart
Journal of the American College of Cardiology, 2011Co-Authors: Daniele Torella, Carla Vicinanza, Georgina M Ellison, Santo Dellegrottaglie, Claudia Perezmartinez, Armando Perez De Prado, Saranya PurushothamanAbstract:Objectives The purpose of this study was to test the ability of insulin-like growth factor (IGF)-1/hepatocyte growth factor (HGF) to activate resident endogenous porcine Cardiac Stem/progenitor Cells (epCSCs) and to promote myocardial repair through a clinically applicable intracoronary injection protocol in a pig model of myocardial infarction (MI) relevant to human disease. Background In rodents, Cardiac Stem/progenitor Cell (CSC) transplantation as well as in situ activation through intramyocardial injection of specific growth factors has been shown to result in myocardial regeneration after acute myocardial infarction (AMI). Methods Acute MI was induced in pigs by a 60-min percutaneous transluminal coronary angiography left anterior descending artery occlusion. The IGF-1 and HGF were co-administered through the infarct-related artery in a single dose (ranging from 0.5 to 2 μg HGF and 2 to 8 μg IGF-1) 30 min after coronary reperfusion. Pigs were sacrificed 21 days later for dose-response relationship evaluation by immunohistopathology or 2 months later for Cardiac function evaluation by Cardiac magnetic resonance imaging. Results The IGF-1/HGF activated c-kit positive–CD45 negative epCSCs and increased their myogenic differentiation in vitro. The IGF-1/HGF, in a dose-dependent manner, improved cardiomyocyte survival, and reduced fibrosis and cardiomyocyte reactive hypertrophy. It significantly increased c-kit positive–CD45 negative epCSC number and fostered the generation of new myocardium (myocytes and microvasculature) in infarcted and peri-infarct/border regions at 21 and 60 days after AMI. The IGF-1/HGF reduced infarct size and improved left ventricular function at 2 months after AMI. Conclusions In an animal model of AMI relevant to the human disease, intracoronary administration of IGF-1/HGF is a practical and effective strategy to reduce pathological Cardiac remodeling, induce myocardial regeneration, and improve ventricular function.
Giacomo Frati - One of the best experts on this subject based on the ideXlab platform.
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differentiation of human adult Cardiac Stem Cells exposed to extremely low frequency electromagnetic fields
Cardiovascular Research, 2009Co-Authors: Roberto Gaetani, Mario Ledda, Lucio Barile, Elvira Forte, Vittoria Ionta, Enrico Demilia, Flavia De Carlo, Isotta Chimenti, Livio Giuliani, Giacomo FratiAbstract:Aims Modulation of Cardiac Stem Cell (CSC) differentiation with minimal manipulation is one of the main goals of clinical applicability of Cell therapy for heart failure. CSCs, obtained from human myocardial bioptic specimens and grown as cardiospheres (CSps) and cardiosphere-derived Cells (CDCs), can engraft and partially regenerate the infarcted myocardium, as previously described. In this paper we assessed the hypothesis that exposure of CSps and CDCs to extremely low-frequency electromagnetic fields (ELF-EMFs), tuned at Ca2+ ion cyclotron energy resonance (Ca2+-ICR), may drive their differentiation towards a Cardiac-specific phenotype. Methods and results A significant increase in the expression of Cardiac markers was observed after 5 days of exposure to Ca2+-ICR in both human CSps and CDCs, as evidenced at transcriptional, translational, and phenotypical levels. Ca2+ mobilization among intraCellular storages was observed and confirmed by compartmentalized analysis of Ca2+ fluorescent probes. Conclusions These results suggest that ELF-EMFs tuned at Ca2+-ICR could be used to drive Cardiac-specific differentiation in adult Cardiac progenitor Cells without any pharmacological or genetic manipulation of the Cells that will be used for therapeutic purposes.
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differentiation of human adult Cardiac Stem Cells exposed to extremely low frequency electromagnetic fields
Cardiovascular Research, 2009Co-Authors: Roberto Gaetani, Mario Ledda, Lucio Barile, Elvira Forte, Vittoria Ionta, Enrico Demilia, Flavia De Carlo, Isotta Chimenti, Livio Giuliani, Giacomo FratiAbstract:Aims Modulation of Cardiac Stem Cell (CSC) differentiation with minimal manipulation is one of the main goals of clinical applicability of Cell therapy for heart failure. CSCs, obtained from human myocardial bioptic specimens and grown as cardiospheres (CSps) and cardiosphere-derived Cells (CDCs), can engraft and partially regenerate the infarcted myocardium, as previously described. In this paper we assessed the hypothesis that exposure of CSps and CDCs to extremely low-frequency electromagnetic fields (ELF-EMFs), tuned at Ca2+ ion cyclotron energy resonance (Ca2+-ICR), may drive their differentiation towards a Cardiac-specific phenotype. Methods and results A significant increase in the expression of Cardiac markers was observed after 5 days of exposure to Ca2+-ICR in both human CSps and CDCs, as evidenced at transcriptional, translational, and phenotypical levels. Ca2+ mobilization among intraCellular storages was observed and confirmed by compartmentalized analysis of Ca2+ fluorescent probes. Conclusions These results suggest that ELF-EMFs tuned at Ca2+-ICR could be used to drive Cardiac-specific differentiation in adult Cardiac progenitor Cells without any pharmacological or genetic manipulation of the Cells that will be used for therapeutic purposes.
Michael Taylor Hensley - One of the best experts on this subject based on the ideXlab platform.
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Cardiac Stem Cell Patch Integrated with Microengineered Blood Vessels Promotes Cardiomyocyte Proliferation and Neovascularization after Acute Myocardial Infarction
ACS applied materials & interfaces, 2018Co-Authors: Ke Huang, Junnan Tang, Michael A. Daniele, Michael Taylor Hensley, Ashlyn T. Young, Tyler A. Allen, Adam C. Vandergriff, Patrick D. Erb, Frances S. LiglerAbstract:Cardiac Stem Cell (CSC) therapy has shown preclinical and clinical evidence for ischemic heart repair but is limited by low Cellular engraftment and survival after transplantation. Previous versions of the Cardiac patch strategy improve Stem Cell engraftment and encourage repair of Cardiac tissue. However, Cardiac patches that can enhance cardiomyogenesis and angiogenesis at the injured site remain elusive. Therapies that target cardiomyocyte proliferation and new blood vessel formation hold great potential for the protection against acute myocardial infarction (MI). Here, we report a new strategy for creating a vascularized Cardiac patch in a facile and modular fashion by leveraging microfluidic hydrodynamic focusing to construct the biomimetic microvessels (BMVs) that include human umbilical vein endothelial Cells (HUVECs) lining the luminal surface and then encapsulating the BMVs in a fibrin gel spiked with human CSCs. We show that the endothelialized BMVs mimicked the natural architecture and function...
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Cardiac Stem Cell Patch Integrated with Microengineered Blood Vessels Promotes Cardiomyocyte Proliferation and Neovascularization after Acute Myocardial Infarction
2018Co-Authors: Ke Huang, Junnan Tang, Michael A. Daniele, Michael Taylor Hensley, Ashlyn T. Young, Tyler A. Allen, Adam C. Vandergriff, Patrick D. Erb, Frances S. LiglerAbstract:Cardiac Stem Cell (CSC) therapy has shown preclinical and clinical evidence for ischemic heart repair but is limited by low Cellular engraftment and survival after transplantation. Previous versions of the Cardiac patch strategy improve Stem Cell engraftment and encourage repair of Cardiac tissue. However, Cardiac patches that can enhance cardiomyogenesis and angiogenesis at the injured site remain elusive. Therapies that target cardiomyocyte proliferation and new blood vessel formation hold great potential for the protection against acute myocardial infarction (MI). Here, we report a new strategy for creating a vascularized Cardiac patch in a facile and modular fashion by leveraging microfluidic hydrodynamic focusing to construct the biomimetic microvessels (BMVs) that include human umbilical vein endothelial Cells (HUVECs) lining the luminal surface and then encapsulating the BMVs in a fibrin gel spiked with human CSCs. We show that the endothelialized BMVs mimicked the natural architecture and function of capillaries and that the resultant vascularized Cardiac patch (BMV–CSC patch) exhibited equivalent release of paracrine factors compared to those of coculture of genuine human CSCs and HUVECs after 7 days of in vitro culture. In a rat model of acute MI, the BMV–CSC patch therapy induced profound mitotic activities of cardiomyocytes in the peri-infarct region 4 weeks post-treatment. A significant increase in myocardial capillary density was noted in the infarcted hearts that received BMV–CSC patch treatment compared to the infarcted hearts treated with conventional CSC patches. The striking therapeutic benefits and the fast and facile fabrication of the BMV–CSC patch make it promising for practical applications. Our findings suggest that the BMV–CSC patch strategy may open up new possibilities for the treatment of ischemic heart injury
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therapeutic microparticles functionalized with biomimetic Cardiac Stem Cell membranes and secretome
Nature Communications, 2017Co-Authors: Junnan Tang, Michael Taylor Hensley, Tyler A. Allen, Adam C. Vandergriff, Deliang Shen, Thomas G Caranasos, Zegen WangAbstract:Stem Cell therapy represents a promising strategy in regenerative medicine. However, Cells need to be carefully preserved and processed before usage. In addition, Cell transplantation carries immunogenicity and/or tumourigenicity risks. Mounting lines of evidence indicate that Stem Cells exert their beneficial effects mainly through secretion (of regenerative factors) and membrane-based Cell-Cell interaction with the injured Cells. Here, we fabricate a synthetic Cell-mimicking microparticle (CMMP) that recapitulates Stem Cell functions in tissue repair. CMMPs carry similar secreted proteins and membranes as genuine Cardiac Stem Cells do. In a mouse model of myocardial infarction, injection of CMMPs leads to the preservation of viable myocardium and augmentation of Cardiac functions similar to Cardiac Stem Cell therapy. CMMPs (derived from human Cells) do not stimulate T-Cell infiltration in immuno-competent mice. In conclusion, CMMPs act as 'synthetic Stem Cells' which mimic the paracrine and biointerfacing activities of natural Stem Cells in therapeutic Cardiac regeneration.
Antonella De Angelis - One of the best experts on this subject based on the ideXlab platform.
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c-kit Haploinsufficiency impairs adult Cardiac Stem Cell growth, myogenicity and myocardial regeneration
Cell Death & Disease, 2019Co-Authors: Iolanda Aquila, Andrew J Smith, Eleonora Cianflone, Antonella De Angelis, Mariangela Scalise, Fabiola Marino, Teresa Mancuso, Andrea Filardo, Donato Cappetta, Konrad UrbanekAbstract:An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident Cardiac c-kit^pos Stem/progenitor Cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kit^Cre knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kit^CreKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kit^CreKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kit^CreCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kit^CreKIs severely affects CSCs myogenic potential. c-kit^CreKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic Cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative Cardiac phenotype of c-kit^CreKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kit^CreKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional Cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.
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Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon?
'Hindawi Limited', 2019Co-Authors: Eleonora Cianflone, Marcello Rota, Cristina Chimenti, Michele Torella, Antonella De Angelis, Antonio P. Beltrami, Konrad Urbanek, Daniele TorellaAbstract:Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic Cellular and molecular changes in Cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of Cardiac aging have been the subject of intense study, the recent discovery that Cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous Cardiac Stem Cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of Cell turnover and renewal, has now been replaced by a dynamic model in which Cardiac Cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo Cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible Cell autonomous process. However, CSC aging could be a programmed Cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract Cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths
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anthracycline cardiomyopathy is mediated by depletion of the Cardiac Stem Cell pool and is rescued by restoration of progenitor Cell function
Circulation, 2010Co-Authors: Antonella De Angelis, Joao Ferreiramartins, Hanqiao Zheng, Toru Hosoda, Laura Marino, Donato Cappetta, Elena Piegari, Amelia Filippelli, L Berrino, Marcello RotaAbstract:Background— Anthracyclines are the most effective drugs available in the treatment of neoplastic diseases; however, they have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure. Methods and Results— Administration of doxorubicin in rats led to a dilated myopathy, heart failure, and death. To test whether the effects of doxorubicin on Cardiac anatomy and function were mediated by alterations in Cardiac progenitor Cells (CPCs), these Cells were exposed to the anthracycline, which increased the formation of reactive oxygen species and caused increases in DNA damage, expression of p53, telomere attrition, and apoptosis. Additionally, doxorubicin resulted in Cell-cycle arrest at the G2/M transition, which led to a significant decrease in CPC growth. Doxorubicin elicited multiple molecular adaptations; the massive apoptotic death that occurred in CPCs in the presence of anthracycline imposed on the surviving CPC pool th...
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diabetes promotes Cardiac Stem Cell aging and heart failure which are prevented by deletion of the p66shc gene
Circulation Research, 2006Co-Authors: Marcello Rota, Antonella De Angelis, Konrad Urbanek, Nicole Lecapitaine, Toru Hosoda, Alessandro Boni, Maria Elena Padiniruegas, Grazia Esposito, Serena Vitale, Claudia CasarsaAbstract:Diabetes leads to a decompensated myopathy, but the etiology of the Cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter Cardiac progenitor Cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66shc gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 Cellular reactions: low levels activate Cell growth, intermediate quantities trigger Cell apoptosis, and high amounts initiate Cell necrosis. CPC replication predominates in dia...
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diabetes promotes Cardiac Stem Cell aging and heart failure which are prevented by deletion of the p66shc gene
Circulation Research, 2006Co-Authors: Marcello Rota, Antonella De Angelis, Konrad Urbanek, Nicole Lecapitaine, Toru Hosoda, Alessandro Boni, Maria Elena Padiniruegas, Grazia Esposito, Serena Vitale, Claudia CasarsaAbstract:Diabetes leads to a decompensated myopathy, but the etiology of the Cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter Cardiac progenitor Cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66shc gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 Cellular reactions: low levels activate Cell growth, intermediate quantities trigger Cell apoptosis, and high amounts initiate Cell necrosis. CPC replication predominates in diabetic p66shc-/-, whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves Cardiac function in diabetic p66shc-/-, suggesting that intact CPCs can effectively counteract the impact of uncontrolled diabetes on the heart. The recognition that p66shc conditions the destiny of CPCs raises the possibility that diabetic cardiomyopathy is a Stem Cell disease in which abnormalities in CPCs define the life and death of the heart. Together, these data point to a genetic link between diabetes and ROS, on the one hand, and CPC survival and growth, on the other.
Marcello Rota - One of the best experts on this subject based on the ideXlab platform.
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Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon?
'Hindawi Limited', 2019Co-Authors: Eleonora Cianflone, Marcello Rota, Cristina Chimenti, Michele Torella, Antonella De Angelis, Antonio P. Beltrami, Konrad Urbanek, Daniele TorellaAbstract:Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic Cellular and molecular changes in Cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of Cardiac aging have been the subject of intense study, the recent discovery that Cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous Cardiac Stem Cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of Cell turnover and renewal, has now been replaced by a dynamic model in which Cardiac Cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo Cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible Cell autonomous process. However, CSC aging could be a programmed Cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract Cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths
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anthracycline cardiomyopathy is mediated by depletion of the Cardiac Stem Cell pool and is rescued by restoration of progenitor Cell function
Circulation, 2010Co-Authors: Antonella De Angelis, Joao Ferreiramartins, Hanqiao Zheng, Toru Hosoda, Laura Marino, Donato Cappetta, Elena Piegari, Amelia Filippelli, L Berrino, Marcello RotaAbstract:Background— Anthracyclines are the most effective drugs available in the treatment of neoplastic diseases; however, they have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure. Methods and Results— Administration of doxorubicin in rats led to a dilated myopathy, heart failure, and death. To test whether the effects of doxorubicin on Cardiac anatomy and function were mediated by alterations in Cardiac progenitor Cells (CPCs), these Cells were exposed to the anthracycline, which increased the formation of reactive oxygen species and caused increases in DNA damage, expression of p53, telomere attrition, and apoptosis. Additionally, doxorubicin resulted in Cell-cycle arrest at the G2/M transition, which led to a significant decrease in CPC growth. Doxorubicin elicited multiple molecular adaptations; the massive apoptotic death that occurred in CPCs in the presence of anthracycline imposed on the surviving CPC pool th...
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diabetes promotes Cardiac Stem Cell aging and heart failure which are prevented by deletion of the p66shc gene
Circulation Research, 2006Co-Authors: Marcello Rota, Antonella De Angelis, Konrad Urbanek, Nicole Lecapitaine, Toru Hosoda, Alessandro Boni, Maria Elena Padiniruegas, Grazia Esposito, Serena Vitale, Claudia CasarsaAbstract:Diabetes leads to a decompensated myopathy, but the etiology of the Cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter Cardiac progenitor Cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66shc gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 Cellular reactions: low levels activate Cell growth, intermediate quantities trigger Cell apoptosis, and high amounts initiate Cell necrosis. CPC replication predominates in dia...
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diabetes promotes Cardiac Stem Cell aging and heart failure which are prevented by deletion of the p66shc gene
Circulation Research, 2006Co-Authors: Marcello Rota, Antonella De Angelis, Konrad Urbanek, Nicole Lecapitaine, Toru Hosoda, Alessandro Boni, Maria Elena Padiniruegas, Grazia Esposito, Serena Vitale, Claudia CasarsaAbstract:Diabetes leads to a decompensated myopathy, but the etiology of the Cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter Cardiac progenitor Cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66shc gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 Cellular reactions: low levels activate Cell growth, intermediate quantities trigger Cell apoptosis, and high amounts initiate Cell necrosis. CPC replication predominates in diabetic p66shc-/-, whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves Cardiac function in diabetic p66shc-/-, suggesting that intact CPCs can effectively counteract the impact of uncontrolled diabetes on the heart. The recognition that p66shc conditions the destiny of CPCs raises the possibility that diabetic cardiomyopathy is a Stem Cell disease in which abnormalities in CPCs define the life and death of the heart. Together, these data point to a genetic link between diabetes and ROS, on the one hand, and CPC survival and growth, on the other.
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Cardiac Stem Cell and myocyte aging heart failure and insulin like growth factor 1 overexpression
Circulation Research, 2004Co-Authors: Daniele Torella, Alyssa Monsen, Marcello Rota, Elias Zias, Daria Nurzynska, Kenneth Walsh, Isao Shiraishi, Ezio Musso, Anthony Rosenzweig, Mark A SussmanAbstract:To determine whether Cellular aging leads to a cardiomyopathy and heart failure, markers of Cellular senescence, Cell death, telomerase activity, telomere integrity, and Cell regeneration were measured in myocytes of aging wild-type mice (WT). These parameters were similarly studied in insulin-like growth factor-1 (IGF-1) transgenic mice (TG) because IGF-1 promotes Cell growth and survival and may delay Cellular aging. Importantly, the consequences of aging on Cardiac Stem Cell (CSC) growth and senescence were evaluated. Gene products implicated in growth arrest and senescence, such as p27 Kip1 , p53, p16 INK4a , and p19 ARF , were detected in myocytes of young WT mice, and their expression increased with age. IGF-1 attenuated the levels of these proteins at all ages. Telomerase activity decreased in aging WT myocytes but increased in TG, paralleling the changes in Akt phosphorylation. Reduction in nuclear phospho-Akt and telomerase resulted in telomere shortening and uncapping in WT myocytes. Senescence and death of CSCs increased with age in WT impairing the growth and turnover of Cells in the heart. DNA damage and myocyte death exceeded Cell formation in old WT, leading to a decreased number of myocytes and heart failure. This did not occur in TG in which CSC-mediated myocyte regeneration compensated for the extent of Cell death preventing ventricular dysfunction. IGF-1 enhanced nuclear phospho-Akt and telomerase delaying Cellular aging and death. The differential response of TG mice to chronological age may result from preservation of functional CSCs undergoing myocyte commitment. In conclusion, senescence of CSCs and myocytes conditions the development of an aging myopathy.