Alessandro Boni
Harvard University
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Featured researches published by Alessandro Boni.
Circulation Research | 2006
Marcello Rota; Nicole LeCapitaine; Toru Hosoda; Alessandro Boni; Antonella De Angelis; Maria Elena Padin-Iruegas; Grazia Esposito; Serena Vitale; Konrad Urbanek; Claudia Casarsa; Marco Giorgio; Thomas F. Lüscher; Pier Giuseppe Pelicci; Piero Anversa; Annarosa Leri; Jan Kajstura
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.
Circulation Research | 2008
Marcello Rota; M. Elena Padin-Iruegas; Yu Misao; Antonella De Angelis; Silvia Maestroni; João Ferreira-Martins; Emanuela Fiumana; Raffaella Rastaldo; Michael L. Arcarese; T Mitchell; Alessandro Boni; Roberto Bolli; Konrad Urbanek; Toru Hosoda; Piero Anversa; Annarosa Leri; Jan Kajstura
Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. These alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. We tested whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by hepatocyte growth factor and insulin-like growth factor-1 invade the scarred myocardium and generate myocytes and coronary vessels improving the hemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful chemoattractant of CPCs, and insulin-like growth factor-1 promotes their proliferation and survival. Injection of CPCs or growth factors led to the replacement of approximately 42% of the scar with newly formed myocardium, attenuated ventricular dilation and prevented the chronic decline in function of the infarcted heart. Cardiac repair was mediated by the ability of CPCs to synthesize matrix metalloproteinases that degraded collagen proteins, forming tunnels within the fibrotic tissue during their migration across the scarred myocardium. New myocytes had a 2n karyotype and possessed 2 sex chromosomes, excluding cell fusion. Clinically, CPCs represent an ideal candidate cell for cardiac repair in patients with chronic heart failure. CPCs may be isolated from myocardial biopsies and, following their expansion in vitro, administered back to the same patients avoiding the adverse effects associated with the use of nonautologous cells. Alternatively, growth factors may be delivered locally to stimulate resident CPCs and promote myocardial regeneration. These forms of treatments could be repeated over time to reduce progressively tissue scarring and expand the working myocardium.
Proceedings of the National Academy of Sciences of the United States of America | 2008
Alessandro Boni; Konrad Urbanek; Angelo Nascimbene; Toru Hosoda; Hanqiao Zheng; Francesca Delucchi; Katsuya Amano; Arantxa Gonzalez; Serena Vitale; Caroline Ojaimi; Roberto Rizzi; Roberto Bolli; Katherine E. Yutzey; Marcello Rota; Jan Kajstura; Piero Anversa; Annarosa Leri
The Notch receptor mediates cell fate decision in multiple organs. In the current work we tested the hypothesis that Nkx2.5 is a target gene of Notch1 and raised the possibility that Notch1 regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPCs) in the niches express Notch1 receptor, and the supporting cells exhibit the Notch ligand Jagged1. The nuclear translocation of Notch1 intracellular domain (N1ICD) up-regulates Nkx2.5 in CPCs and promotes the formation of cycling myocytes in vitro. N1ICD and RBP-Jk form a protein complex, which in turn binds to the Nkx2.5 promoter initiating transcription and myocyte differentiation. In contrast, transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway. Importantly, inhibition of Notch1 in infarcted mice impairs the commitment of resident CPCs to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notch1 favors the early specification of CPCs to the myocyte phenotype but maintains the newly formed cells in a highly proliferative state. Dividing Nkx2.5-positive myocytes correspond to transit amplifying cells, which condition the replicative capacity of the heart. In conclusion, Notch1 may have critical implications in the control of heart homeostasis and its adaptation to pathologic states.
Circulation Research | 2005
Marcello Rota; Alessandro Boni; Konrad Urbanek; Maria Elena Padin-Iruegas; Tymoteusz J Kajstura; Giuseppe Fiore; Hajime Kubo; Edmund H. Sonnenblick; Ezio Musso; Steve R. Houser; Annarosa Leri; Mark A. Sussman; Piero Anversa
Cytoplasmic overexpression of Akt in the heart results in a myopathy characterized by organ and myocyte hypertrophy. Conversely, nuclear-targeted Akt does not lead to cardiac hypertrophy, but the cellular basis of this distinct heart phenotype remains to be determined. Similarly, whether nuclear-targeted Akt affects ventricular performance and mechanics, calcium metabolism, and electrical properties of myocytes is unknown. Moreover, whether the expression and state of phosphorylation of regulatory proteins implicated in calcium cycling and myocyte contractility are altered in nuclear-targeted Akt has not been established. We report that nuclear overexpression of Akt does not modify cardiac size and shape but results in an increased number of cardiomyocytes, which are smaller in volume. Additionally, the heart possesses enhanced systolic and diastolic function, which is paralleled by increased myocyte performance. Myocyte shortening and velocity of shortening and relengthening are increased in transgenic mice and are coupled with a more efficient reuptake of calcium by the sarcoplasmic reticulum (SR). This process increases calcium loading of the SR during relengthening. The enhanced SR function appears to be mediated by an increase in SR Ca2+-ATPase2a activity sustained by a higher degree of phosphorylation of phospholamban. This posttranslational modification was associated with an increase in phospho–protein kinase A and a decrease in protein phosphatase-1. Together, these observations provide a plausible biochemical mechanism for the potentiation of myocyte and ventricular function in Akt transgenic mice. Therefore, nuclear-targeted Akt in myocytes may have important implications for the diseased heart.
Proceedings of the National Academy of Sciences of the United States of America | 2006
Konrad Urbanek; Daniela Cesselli; Marcello Rota; Angelo Nascimbene; Antonella De Angelis; Toru Hosoda; Claudia Bearzi; Alessandro Boni; Roberto Bolli; Jan Kajstura; Piero Anversa; Annarosa Leri
Cardiovascular Regeneration and Stem Cell Therapy | 2007
Annarosa Leri; Alessandro Boni; Robert W. Siggins; Angelo Nascimbene; Toru Hosoda
Circulation | 2008
Marcello Rota; Maria Elena Padin-Iruegas; Yu Misao; Antonella De Angelis; Silvia Maestroni; Alessandro Boni; Joao Ferreira-Martins; Roberto Bolli; Konrad Urbanek; Toru Hosoda; Piero Anversa; Annarosa Leri; Jan Kajstura
Circulation | 2008
Maria Elena Padin-Iruegas; Marcello Rota; Yu Misao; Antonella De Angelis; Silvia Maestroni; Granzia Esposito; Alessandro Boni; Joao Ferreira-Martins; Roberto Bolli; Konrad Urbanek; Toru Hosoda; Piero Anversa; Annarosa Leri; Jan Kajstura
Circulation | 2007
Francesca Delucchi; Konrad Urbanek; Alessandro Boni; Robert W. Siggins; Katsuya Amano; Grazia Iaffaldano; Saori Yasuzawa-Amano; Nicole LeCapitaine; Serena Vitale; Arantxa González; Andrea Di Marco; Irina Trofimova; Roberto Rizzi; Yu Misao; Piero Anversa; Jan Kajstura; Annarosa Leri
Circulation | 2007
Alessandro Boni; Angelo Nascimbene; Robert W. Siggins; Konrad Urbanek; Katsuya Amano; Francesca Delucchi; Saori Yasuzawa-Amano; Nicole LeCapitaine; Irina Trofimova; Andrea Di Marco; Serena Vitale; Narissa Small; Federico Mosna; Arantxa González; Ornella Rimoldi; Jan Kajstura; Piero Anversa; Annarosa Leri