Toru Hosoda

Publications (44)445.52 Total impact

• Source

  Available from: Federica del Monte

  Dataset: 118380 supplemental material

  Jan Kajstura, Marcello Rota, Donato Cappetta, Barbara Ogórek, Christian Arranto, Yingnan Bai, João Ferreira-Martins, Sergio Signore, Fumihiro Sanada, Alex Matsuda, [......], Claudia Fiorini, David A D'Alessandro, Robert E Michler, Federica Del Monte, Toru Hosoda, Mark A Perrella, Annarosa Leri, Bruce A Buchholz, Joseph Loscalzo, Piero Anversa
• Article: Dissecting the Molecular Relationship Among Various Cardiogenic Progenitor Cells.

  Devaveena Dey, Leng Han, Michael Bauer, Fumihiro Sanada, Angelos Oikonomopoulos, Toru Hosoda, Kazumasa Unno, Patricia De Almeida, Annarosa Leri, Joseph C Wu
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  ABSTRACT: Rationale: Multiple progenitors derived from the heart and bone marrow have been utilized for cardiac repair. Despite this, not much is known about the molecular identity and relationship among these progenitors. To develop a robust stem cell therapy for the heart, it is critical to understand the molecular identity of the multiple 'cardiogenic progenitor cells' (CPCs). Objective: This study is the first report of high throughput transcriptional profiling of CPCs carried out on an identical platform. Methods and Results: Microarray based transcriptional profiling was carried out for three cardiac (ckit+, Sca1+, side population) and two bone marrow (ckit+, mesenchymal stem cell) progenitors, obtained from age- and sex-matched wild type C57BL/6 mice. Analysis indicated that cardiac-derived ckit+ population was very distinct from Sca1+ and SP cells in the downregulation of genes encoding for cell-cell and matrix adhesion proteins, and in the upregulation of developmental genes. Significant enrichment of transcripts involved in DNA replication and repair was observed in bone marrow (BM)-derived progenitors. The BM ckit+ cells appeared to have the least correlation with the other progenitors, with enrichment of immature neutrophil specific molecules. Conclusions: Our study indicates that cardiac ckit+ cells represent the most primitive population in the rodent heart. Primitive cells of cardiac versus BM origin differ significantly with respect to stemness and cardiac lineage-specific genes, and molecules involved in DNA replication and repair. The detailed molecular profile of progenitors reported here will serve as a useful reference to determine the molecular identity of progenitors used in future preclinical and clinical studies.
  Circulation Research 03/2013; · 9.49 Impact Factor
• Source

  Available from: Federica del Monte

  Article: Cardiomyogenesis in the aging and failing human heart.

  Jan Kajstura, Marcello Rota, Donato Cappetta, Barbara Ogórek, Christian Arranto, Yingnan Bai, João Ferreira-Martins, Sergio Signore, Fumihiro Sanada, Alex Matsuda, [......], Claudia Fiorini, David A D'Alessandro, Robert E Michler, Federica Del Monte, Toru Hosoda, Mark A Perrella, Annarosa Leri, Bruce A Buchholz, Joseph Loscalzo, Piero Anversa
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  ABSTRACT: Two opposite views of cardiac growth are currently held; one views the heart as a static organ characterized by a large number of cardiomyocytes that are present at birth and live as long as the organism, and the other views the heart a highly plastic organ in which the myocyte compartment is restored several times during the course of life. The average age of cardiomyocytes, vascular endothelial cells (ECs), and fibroblasts and their turnover rates were measured by retrospective (14)C birth dating of cells in 19 normal hearts 2 to 78 years of age and in 17 explanted failing hearts 22 to 70 years of age. We report that the human heart is characterized by a significant turnover of ventricular myocytes, ECs, and fibroblasts, physiologically and pathologically. Myocyte, EC, and fibroblast renewal is very high shortly after birth, decreases during postnatal maturation, remains relatively constant in the adult organ, and increases dramatically with age. From 20 to 78 years of age, the adult human heart entirely replaces its myocyte, EC, and fibroblast compartment ≈8, ≈6, and ≈8 times, respectively. Myocyte, EC, and fibroblast regeneration is further enhanced with chronic heart failure. The human heart is a highly dynamic organ that retains a remarkable degree of plasticity throughout life and in the presence of chronic heart failure. However, the ability to regenerate cardiomyocytes, vascular ECs, and fibroblasts cannot prevent the manifestations of myocardial aging or oppose the negative effects of ischemic and idiopathic dilated cardiomyopathy.
  Circulation 09/2012; 126(15):1869-81. · 14.74 Impact Factor
• Article: Tracking chromatid segregation to identify human cardiac stem cells that regenerate extensively the infarcted myocardium.

  Jan Kajstura, Yingnan Bai, Donato Cappetta, Junghyun Kim, Christian Arranto, Fumihiro Sanada, Domenico D'Amario, Alex Matsuda, Silvana Bardelli, João Ferreira-Martins, Toru Hosoda, Annarosa Leri, Marcello Rota, Joseph Loscalzo, Piero Anversa
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  ABSTRACT: Rationale: According to the immortal DNA strand hypothesis, dividing stem cells selectively segregate chromosomes carrying the old template DNA, opposing accumulation of mutations resulting from nonrepaired replication errors and attenuating telomere shortening. Objective: Based on the premise of the immortal DNA strand hypothesis, we propose that stem cells retaining the old DNA would represent the most powerful cells for myocardial regeneration. Methods and Results: Division of human cardiac stem cells (hCSCs) by nonrandom and random segregation of chromatids was documented by clonal assay of bromodeoxyuridine-tagged hCSCs. Additionally, their growth properties were determined by a series of in vitro and in vivo studies. We report that a small class of hCSCs retain during replication the mother DNA and generate 2 daughter cells, which carry the old and new DNA, respectively. hCSCs with immortal DNA form a pool of nonsenescent cells with longer telomeres and higher proliferative capacity. The self-renewal and long-term repopulating ability of these cells was shown in serial-transplantation assays in the infarcted heart; these cells created a chimeric organ, composed of spared rat and regenerated human cardiomyocytes and coronary vessels, leading to a remarkable restoration of cardiac structure and function. The documentation that hCSCs divide by asymmetrical and symmetrical chromatid segregation supports the view that the human heart is a self-renewing organ regulated by a compartment of resident hCSCs. Conclusions: The impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this stem cell class for the management of heart failure in humans.
  Circulation Research 07/2012; 111(7):894-906. · 9.49 Impact Factor
• Article: Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells.

  João Ferreira-Martins, Barbara Ogórek, Donato Cappetta, Alex Matsuda, Sergio Signore, Domenico D'Amario, James Kostyla, Elisabeth Steadman, Noriko Ide-Iwata, Fumihiro Sanada, Grazia Iaffaldano, Sergio Ottolenghi, Toru Hosoda, Annarosa Leri, Jan Kajstura, Piero Anversa, Marcello Rota
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  ABSTRACT: Embryonic and fetal myocardial growth is characterized by a dramatic increase in myocyte number, but whether the expansion of the myocyte compartment is dictated by activation and commitment of resident cardiac stem cells (CSCs), division of immature myocytes or both is currently unknown. In this study, we tested whether prenatal cardiac development is controlled by activation and differentiation of CSCs and whether division of c-kit-positive CSCs in the mouse heart is triggered by spontaneous Ca(2+) oscillations. We report that embryonic-fetal c-kit-positive CSCs are self-renewing, clonogenic and multipotent in vitro and in vivo. The growth and commitment of c-kit-positive CSCs is responsible for the generation of the myocyte progeny of the developing heart. The close correspondence between values computed by mathematical modeling and direct measurements of myocyte number at E9, E14, E19 and 1 day after birth strongly suggests that the organogenesis of the embryonic heart is dependent on a hierarchical model of cell differentiation regulated by resident CSCs. The growth promoting effects of c-kit-positive CSCs are triggered by spontaneous oscillations in intracellular Ca(2+), mediated by IP3 receptor activation, which condition asymmetrical stem cell division and myocyte lineage specification. Myocyte formation derived from CSC differentiation is the major determinant of cardiac growth during development. Division of c-kit-positive CSCs in the mouse is promoted by spontaneous Ca(2+) spikes, which dictate the pattern of stem cell replication and the generation of a myocyte progeny at all phases of prenatal life and up to one day after birth.
  Circulation Research 03/2012; 110(5):701-15. · 9.49 Impact Factor
• Article: Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.

  Roberto Bolli, Atul R Chugh, Domenico D'Amario, John H Loughran, Marcus F Stoddard, Sohail Ikram, Garth M Beache, Stephen G Wagner, Annarosa Leri, Toru Hosoda, Fumihiro Sanada, Julius B Elmore, Polina Goichberg, Donato Cappetta, Naresh K Solankhi, Ibrahim Fahsah, D Gregg Rokosh, Mark S Slaughter, Jan Kajstura, Piero Anversa
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  ABSTRACT: c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. University of Louisville Research Foundation and National Institutes of Health.
  The Lancet 11/2011; 378(9806):1847-57. · 38.28 Impact Factor
• Source

  Available from: Antonio Paolo Beltrami

  Article: Effects of age and heart failure on human cardiac stem cell function.

  Daniela Cesselli, Antonio P Beltrami, Federica D'Aurizio, Patrizia Marcon, Natascha Bergamin, Barbara Toffoletto, Maura Pandolfi, Elisa Puppato, Laura Marino, Sergio Signore, [......], Silvano Piazza, Luigi Marchionni, Claudia Fiorini, Claudio Schneider, Toru Hosoda, Marcello Rota, Jan Kajstura, Piero Anversa, Carlo A Beltrami, Annarosa Leri
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  ABSTRACT: Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21(Cip1) and p16(INK4a) expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy.
  American Journal Of Pathology 07/2011; 179(1):349-66. · 4.89 Impact Factor
• Article: Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration.

  Domenico D'Amario, Mauricio C Cabral-Da-Silva, Hanqiao Zheng, Claudia Fiorini, Polina Goichberg, Elisabeth Steadman, João Ferreira-Martins, Fumihiro Sanada, Marco Piccoli, Donato Cappetta, David A D'Alessandro, Robert E Michler, Toru Hosoda, Luigi Anastasia, Marcello Rota, Annarosa Leri, Piero Anversa, Jan Kajstura
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  ABSTRACT: Age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart. Insulin-like growth factor (IGF)-1, IGF-2, and angiotensin II (Ang II), as well as their receptors, IGF-1R, IGF-2R, and AT1R, were characterized in c-kit(+) hCSCs to establish whether these systems would allow us to separate hCSC classes with different growth reserve in the aging and diseased myocardium. C-kit(+) hCSCs were collected from myocardial samples obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac surgery for coronary artery disease. The expression of IGF-1R in hCSCs recognized a young cell phenotype defined by long telomeres, high telomerase activity, enhanced cell proliferation, and attenuated apoptosis. In addition to IGF-1, IGF-1R(+) hCSCs secreted IGF-2 that promoted myocyte differentiation. Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, identified senescent hCSCs with impaired growth reserve and increased susceptibility to apoptosis. The ability of IGF-1R(+) hCSCs to regenerate infarcted myocardium was then compared with that of unselected c-kit(+) hCSCs. IGF-1R(+) hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of IGF-1R(+) hCSCs with IGF-2 resulted in the formation of more mature myocytes and superior recovery of ventricular structure. hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which are potent modulators of stem cell replication, commitment to the myocyte lineage, and myocyte differentiation, which points to this hCSC subset as the ideal candidate cell for the management of human heart failure.
  Circulation Research 06/2011; 108(12):1467-81. · 9.49 Impact Factor
• Article: Identification of a coronary stem cell in the human heart.

  Annarosa Leri, Toru Hosoda, Jan Kajstura, Piero Anversa, Marcello Rota
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  ABSTRACT: Human ischemic cardiomyopathy is characterized by de novo cardiomyogenesis, which is limited to the surviving portion of the ventricle, and by organ hypertrophy that develops as a chronic response to ischemic injury. Although myocyte hypertrophy and myocyte regeneration restore the original myocardial mass, the coronary vasculature remains defective and the extent and regulation of myocardial perfusion are severely impaired. Recently, vascular stem cells (VSCs) have been identified in the coronary circulation. VSCs express c-kit and the vascular endothelial growth factor receptor-2, KDR. These cells are self-renewing, clonogenic, and multipotent in vitro and in vivo. In animal models of critical coronary artery stenosis, VSCs form large conductive coronary arteries and their distal branches. This degree of vasculogenesis replaces partly the function of the occluded coronary artery improving myocardial perfusion and positively interfering with the development of the post-infarction myopathy. Cell therapy directed to the restoration of the integrity of the coronary circulation, the replacement of atherosclerotic coronary vessels, or both, would change dramatically the goal of cell therapy for the ischemic heart: the prevention of myocardial injury would become the end-point of cell therapy rather than the partial recovery of established damage.
  Journal of Molecular Medicine 05/2011; 89(10):947-59. · 4.67 Impact Factor
• Article: Evidence for human lung stem cells.

  Jan Kajstura, Marcello Rota, Sean R Hall, Toru Hosoda, Domenico D'Amario, Fumihiro Sanada, Hanqiao Zheng, Barbara Ogórek, Carlos Rondon-Clavo, João Ferreira-Martins, [......], Kathleen J Haley, Silvana Bardelli, Hussein Rayatzadeh, Xiaoli Liu, Federico Quaini, Ronglih Liao, Annarosa Leri, Mark A Perrella, Joseph Loscalzo, Piero Anversa
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  ABSTRACT: Although progenitor cells have been described in distinct anatomical regions of the lung, description of resident stem cells has remained elusive. Surgical lung-tissue specimens were studied in situ to identify and characterize human lung stem cells. We defined their phenotype and functional properties in vitro and in vivo. Human lungs contain undifferentiated human lung stem cells nested in niches in the distal airways. These cells are self-renewing, clonogenic, and multipotent in vitro. After injection into damaged mouse lung in vivo, human lung stem cells form human bronchioles, alveoli, and pulmonary vessels integrated structurally and functionally with the damaged organ. The formation of a chimeric lung was confirmed by detection of human transcripts for epithelial and vascular genes. In addition, the self-renewal and long-term proliferation of human lung stem cells was shown in serial-transplantation assays. Human lungs contain identifiable stem cells. In animal models, these cells participate in tissue homeostasis and regeneration. They have the undemonstrated potential to promote tissue restoration in patients with lung disease. (Funded by the National Institutes of Health.).
  New England Journal of Medicine 05/2011; 364(19):1795-806. · 53.30 Impact Factor
• Article: Human cardiac stem cell differentiation is regulated by a mircrine mechanism.

  Toru Hosoda, Hanqiao Zheng, Mauricio Cabral-da-Silva, Fumihiro Sanada, Noriko Ide-Iwata, Barbara Ogórek, João Ferreira-Martins, Christian Arranto, Domenico D'Amario, Federica del Monte, Konrad Urbanek, David A D'Alessandro, Robert E Michler, Piero Anversa, Marcello Rota, Jan Kajstura, Annarosa Leri
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  ABSTRACT: Cardiac stem cells (CSCs) delivered to the infarcted heart generate a large number of small fetal-neonatal cardiomyocytes that fail to acquire the differentiated phenotype. However, the interaction of CSCs with postmitotic myocytes results in the formation of cells with adult characteristics. On the basis of results of in vitro and in vivo assays, we report that the commitment of human CSCs (hCSCs) to the myocyte lineage and the generation of mature working cardiomyocytes are influenced by microRNA-499 (miR-499), which is barely detectable in hCSCs but is highly expressed in postmitotic human cardiomyocytes. miR-499 traverses gap junction channels and translocates to structurally coupled hCSCs favoring their differentiation into functionally competent cells. Expression of miR-499 in hCSCs represses the miR-499 target genes Sox6 and Rod1, enhancing cardiomyogenesis in vitro and after infarction in vivo. Although cardiac repair was detected in all cell-treated infarcted hearts, the aggregate volume of the regenerated myocyte mass and myocyte cell volume were greater in animals injected with hCSCs overexpressing miR-499. Treatment with hCSCs resulted in an improvement in ventricular function, consisting of a better preservation of developed pressure and positive and negative dP/dt after infarction. An additional positive effect on cardiac performance occurred with miR-499, pointing to enhanced myocyte differentiation/hypertrophy as the mechanism by which miR-499 potentiated the restoration of myocardial mass and function in the infarcted heart. The recognition that miR-499 promotes the differentiation of hCSCs into mechanically integrated cardiomyocytes has important clinical implications for the treatment of human heart failure.
  Circulation 03/2011; 123(12):1287-96. · 14.74 Impact Factor
• Article: The ephrin A1-EphA2 system promotes cardiac stem cell migration after infarction.

  Polina Goichberg, Yingnan Bai, Domenico D'Amario, João Ferreira-Martins, Claudia Fiorini, Hanqiao Zheng, Sergio Signore, Federica del Monte, Sergio Ottolenghi, David A D'Alessandro, Robert E Michler, Toru Hosoda, Piero Anversa, Jan Kajstura, Marcello Rota, Annarosa Leri
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  ABSTRACT: Understanding the mechanisms that regulate trafficking of human cardiac stem cells (hCSCs) may lead to development of new therapeutic approaches for the failing heart. We tested whether the motility of hCSCs in immunosuppressed infarcted animals is controlled by the guidance system that involves the interaction of Eph receptors with ephrin ligands. Within the cardiac niches, cardiomyocytes expressed preferentially the ephrin A1 ligand, whereas hCSCs possessed the EphA2 receptor. Treatment of hCSCs with ephrin A1 resulted in the rapid internalization of the ephrin A1-EphA2 complex, posttranslational modifications of Src kinases, and morphological changes consistent with the acquisition of a motile cell phenotype. Ephrin A1 enhanced the motility of hCSCs in vitro, and their migration in vivo following acute myocardial infarction. At 2 weeks after infarction, the volume of the regenerated myocardium was 2-fold larger in animals injected with ephrin A1-activated hCSCs than in animals receiving control hCSCs; this difference was dictated by a greater number of newly formed cardiomyocytes and coronary vessels. The increased recovery in myocardial mass with ephrin A1-treated hCSCs was characterized by further restoration of cardiac function and by a reduction in arrhythmic events. Ephrin A1 promotes the motility of EphA2-positive hCSCs, facilitates their migration to the area of damage, and enhances cardiac repair. Thus, in situ stimulation of resident hCSCs with ephrin A1 or their ex vivo activation before myocardial delivery improves cell targeting to sites of injury, possibly providing a novel strategy for the management of the diseased heart.
  Circulation Research 03/2011; 108(9):1071-83. · 9.49 Impact Factor
• Article: Functionally competent cardiac stem cells can be isolated from endomyocardial biopsies of patients with advanced cardiomyopathies.

  Domenico D'Amario, Claudia Fiorini, Patricia M Campbell, Polina Goichberg, Fumihiro Sanada, Hanqiao Zheng, Toru Hosoda, Marcello Rota, John M Connell, Robert P Gallegos, Frederick G Welt, Michael M Givertz, Richard N Mitchell, Annarosa Leri, Jan Kajstura, Marc A Pfeffer, Piero Anversa
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  ABSTRACT: Two categories of cardiac stem cells (CSCs) with predominantly myogenic (mCSC) and vasculogenic (vCSC) properties have been characterized in the human heart. However, it is unknown whether functionally competent CSCs of both classes are present in the myocardium of patients affected by end-stage cardiac failure, and whether these cells can be harvested from relatively small myocardial samples. To establish whether a clinically relevant number of mCSCs and vCSCs can be isolated and expanded from endomyocardial biopsies of patients undergoing cardiac transplantation or left ventricular assist device implantation. Endomyocardial biopsies were collected with a bioptome from the right side of the septum of explanted hearts or the apical LV core at the time of left ventricular assist device implantation. Two to 5 biopsies from each patient were enzymatically dissociated, and, after expansion, cells were sorted for c-kit (mCSCs) or c-kit and KDR (vCSCs) and characterized. mCSCs and vCSCs constituted 97% and 3% of the c-kit population, respectively. Population doubling time averaged 27 hours in mCSCs and vCSCs; 5×10(6) mCSCs and vCSCs were obtained in 28 and 41 days, respectively. Both CSC classes possessed significant growth reserve as documented by high telomerase activity and relatively long telomeres. mCSCs formed mostly cardiomyocytes, and vCSCs endothelial and smooth muscle cells. The growth properties of mCSCs and vCSCs isolated from endomyocardial biopsies from patients with advanced heart failure were comparable to those obtained previously from larger myocardial samples of patients undergoing elective cardiac surgery.
  Circulation Research 02/2011; 108(7):857-61. · 9.49 Impact Factor
• Article: Myocyte turnover in the aging human heart.

  Jan Kajstura, Narasimman Gurusamy, Barbara Ogórek, Polina Goichberg, Carlos Clavo-Rondon, Toru Hosoda, Domenico D'Amario, Silvana Bardelli, Antonio P Beltrami, Daniela Cesselli, Rossana Bussani, Federica del Monte, Federico Quaini, Marcello Rota, Carlo A Beltrami, Bruce A Buchholz, Annarosa Leri, Piero Anversa
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  ABSTRACT: The turnover of cardiomyocytes in the aging female and male heart is currently unknown, emphasizing the need to define human myocardial biology. The effects of age and gender on the magnitude of myocyte regeneration and the origin of newly formed cardiomyocytes were determined. The interaction of myocyte replacement, cellular senescence, growth inhibition, and apoptosis was measured in normal female (n=32) and male (n=42) human hearts collected from patients 19 to 104 years of age who died from causes other than cardiovascular diseases. A progressive loss of telomeric DNA in human cardiac stem cells (hCSCs) occurs with aging and the newly formed cardiomyocytes inherit short telomeres and rapidly reach the senescent phenotype. Our data provide novel information on the superior ability of the female heart to sustain the multiple variables associated with the development of the senescent myopathy. At all ages, the female heart is equipped with a larger pool of functionally competent hCSCs and younger myocytes than the male myocardium. The replicative potential is higher and telomeres are longer in female hCSCs than in male hCSCs. In the female heart, myocyte turnover occurs at a rate of 10%, 14%, and 40% per year at 20, 60, and 100 years of age, respectively. Corresponding values in the male heart are 7%, 12%, and 32% per year, documenting that cardiomyogenesis involves a large and progressively increasing number of parenchymal cells with aging. From 20 to 100 years of age, the myocyte compartment is replaced 15 times in women and 11 times in men. The human heart is a highly dynamic organ regulated by a pool of resident hCSCs that modulate cardiac homeostasis and condition organ aging.
  Circulation Research 11/2010; 107(11):1374-86. · 9.49 Impact Factor
• Article: Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.

  Konrad Urbanek, Mauricio Castro Cabral-da-Silva, Noriko Ide-Iwata, Silvia Maestroni, Francesca Delucchi, Hanqiao Zheng, João Ferreira-Martins, Barbara Ogórek, Domenico D'Amario, Michael Bauer, Gianpaolo Zerbini, Marcello Rota, Toru Hosoda, Ronglih Liao, Piero Anversa, Jan Kajstura, Annarosa Leri
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  ABSTRACT: Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation. In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment. We have found that the newborn heart contains a population of c-kit-positive CSCs that are lineage negative, self-renewing, and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5, indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs significantly expanded the proportion of transit-amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a gamma-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality rates. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes, which resulted in a 54% decrease in myocyte number. After cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored. Notch1 signaling is a critical determinant of CSC growth and differentiation; when this cascade of events is altered, cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented, and a life-threatening myopathy supervenes.
  Circulation Research 08/2010; 107(3):429-41. · 9.49 Impact Factor
• Source

  Available from: Shira Perl

  Article: Cardiomyogenesis in the adult human heart.

  Jan Kajstura, Konrad Urbanek, Shira Perl, Toru Hosoda, Hanqiao Zheng, Barbara Ogórek, João Ferreira-Martins, Polina Goichberg, Carlos Rondon-Clavo, Fumihiro Sanada, Domenico D'Amario, Marcello Rota, Federica Del Monte, Donald Orlic, John Tisdale, Annarosa Leri, Piero Anversa
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  ABSTRACT: The ability of the human heart to regenerate large quantities of myocytes remains controversial, and the extent of myocyte renewal claimed by different laboratories varies from none to nearly 20% per year. To address this issue, we examined the percentage of myocytes, endothelial cells, and fibroblasts labeled by iododeoxyuridine in postmortem samples obtained from cancer patients who received the thymidine analog for therapeutic purposes. Additionally, the potential contribution of DNA repair, polyploidy, and cell fusion to the measurement of myocyte regeneration was determined. The fraction of myocytes labeled by iododeoxyuridine ranged from 2.5% to 46%, and similar values were found in fibroblasts and endothelial cells. An average 22%, 20%, and 13% new myocytes, fibroblasts, and endothelial cells were generated per year, suggesting that the lifespan of these cells was approximately 4.5, 5, and 8 years, respectively. The newly formed cardiac cells showed a fully differentiated adult phenotype and did not express the senescence-associated protein p16(INK4a). Moreover, measurements by confocal microscopy and flow cytometry documented that the human heart is composed predominantly of myocytes with 2n diploid DNA content and that tetraploid and octaploid nuclei constitute only a small fraction of the parenchymal cell pool. Importantly, DNA repair, ploidy formation, and cell fusion were not implicated in the assessment of myocyte regeneration. Our findings indicate that the human heart has a significant growth reserve and replaces its myocyte and nonmyocyte compartment several times during the course of life.
  Circulation Research 07/2010; 107(2):305-15. · 9.49 Impact Factor
• Article: Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function.

  Antonella De Angelis, Elena Piegari, Donato Cappetta, Laura Marino, Amelia Filippelli, Liberato Berrino, João Ferreira-Martins, Hanqiao Zheng, Toru Hosoda, Marcello Rota, Konrad Urbanek, Jan Kajstura, Annarosa Leri, Francesco Rossi, Piero Anversa
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  ABSTRACT: 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. 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 the activation of several pathways aimed at preservation of the primitive state, cell division, lineage differentiation, and repair of damaged DNA. To establish whether delivery of syngeneic progenitor cells opposed the progression of doxorubicin cardiotoxicity, enhanced green fluorescent protein-labeled CPCs were injected in the failing myocardium; this treatment promoted regeneration of cardiomyocytes and vascular structures, which improved ventricular performance and rate of animal survival. Our results raise the possibility that autologous CPCs can be obtained before antineoplastic drugs are given to cancer patients and subsequently administered to individuals who are particularly sensitive to the cardiotoxicity of these agents for prevention or management of heart failure.
  Circulation 01/2010; 121(2):276-92. · 14.74 Impact Factor
• Article: Mechanisms of myocardial regeneration.

  Toru Hosoda, Jan Kajstura, Annarosa Leri, Piero Anversa
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  ABSTRACT: The plasticity of bone marrow-derived progenitor cells (BMPCs) and their ability to acquire the myocyte lineage and regenerate dead myocardium after infarction has been challenged. Similarly, although several laboratories have identified cardiac progenitor cells (CPCs), the controversy concerning myocyte regeneration in the adult heart has not been resolved. The therapeutic efficacy of these 2 classes of progenitor cells depends on their ability to (1)survive in the hostile milieu of the damaged heart, (2)engraft within the myocardium and (3)grow and differentiate. BMPCs may have a growth potential that is superior to that of CPCs, but transdifferentiation could affect this characteristic and CPCs may constitute a more powerful form of therapy for cardiac repair. The process of transdifferentiation may alter the growth behavior of BMPCs, which may result in losing part of their capability of dividing through alterations of the telomere-telomerase system, premature cellular senescence and apoptosis. Moreover, myocytes derived from BMPCs may possess inherent limitations in the acquisition of the adult phenotype. The opposite may also be true and BMPCs may retain a stronger regenerative capacity than CPCs, representing the most appropriate cells for the damaged heart even after transdifferentiation. Ultimately, the question to be addressed is whether BMPCs are superior, equal or inferior to CPCs for the regeneration of cardiomyocytes and coronary vessels in acute and chronic ischemic heart failure. (Circ J 2010; 74: 13 - 17).
  Circulation Journal 11/2009; 74(1):13-7. · 3.77 Impact Factor
• Article: Spontaneous calcium oscillations regulate human cardiac progenitor cell growth.

  João Ferreira-Martins, Carlos Rondon-Clavo, Derin Tugal, Justin A Korn, Roberto Rizzi, Maria Elena Padin-Iruegas, Sergio Ottolenghi, Antonella De Angelis, Konrad Urbanek, Noriko Ide-Iwata, Domenico D'Amario, Toru Hosoda, Annarosa Leri, Jan Kajstura, Piero Anversa, Marcello Rota
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  ABSTRACT: The adult heart possesses a pool of progenitor cells stored in myocardial niches, but the mechanisms involved in the activation of this cell compartment are currently unknown. Ca2+ promotes cell growth raising the possibility that changes in intracellular Ca2+ initiate division of c-kit-positive human cardiac progenitor cells (hCPCs) and determine their fate. Ca2+ oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca2+. These findings were confirmed in the heart of transgenic mice in which enhanced green fluorescent protein was under the control of the c-kit promoter. Ca2+ oscillations in hCPCs were regulated by the release of Ca2+ from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca2+ by the sarco-/endoplasmic reticulum Ca2+ pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na+-Ca2+ exchanger, store-operated Ca2+ channels and plasma membrane Ca2+ pump were present and functional in hCPCs, they had no direct effects on Ca2+ oscillations. Conversely, Ca2+ oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca2+ oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca2+ oscillations in hCPCs before their intramyocardial delivery to infarcted hearts was associated with enhanced engraftment and expansion of these cells promoting the generation of a large myocyte progeny. IP3R-mediated Ca2+ mobilization control hCPC growth and their regenerative potential.
  Circulation Research 10/2009; 105(8):764-74. · 9.49 Impact Factor
• Article: Clonality of mouse and human cardiomyogenesis in vivo.

  Toru Hosoda, Domenico D'Amario, Mauricio Castro Cabral-Da-Silva, Hanqiao Zheng, M Elena Padin-Iruegas, Barbara Ogorek, João Ferreira-Martins, Saori Yasuzawa-Amano, Katsuya Amano, Noriko Ide-Iwata, Wei Cheng, Marcello Rota, Konrad Urbanek, Jan Kajstura, Piero Anversa, Annarosa Leri
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  ABSTRACT: An analysis of the clonality of cardiac progenitor cells (CPCs) and myocyte turnover in vivo requires genetic tagging of the undifferentiated cells so that the clonal marker of individual mother cells is traced in the specialized progeny. CPC niches in the atria and apex of the mouse heart were infected with a lentivirus carrying EGFP, and the destiny of the tagged cells was determined 1-5 months later. A common integration site was identified in isolated CPCs, cardiomyocytes, endothelial cells (ECs), and fibroblasts, documenting CPC self-renewal and multipotentiality and the clonal origin of the differentiated cell populations. Subsequently, the degree of EGFP-lentiviral infection of CPCs was evaluated 2-4 days after injection, and the number of myocytes expressing the reporter gene was measured 6 months later. A BrdU pulse-chasing protocol was also introduced as an additional assay for the analysis of myocyte turnover. Over a period of 6 months, each EGFP-positive CPC divided approximately eight times generating 230 cardiomyocytes; this value was consistent with the number of newly formed cells labeled by BrdU. To determine whether, human CPCs (hCPCs) are self-renewing and multipotent, these cells were transduced with the EGFP-lentivirus and injected after acute myocardial infarction in immunosuppressed rats. hCPCs, myocytes, ECs, and fibroblasts collected from the regenerated myocardium showed common viral integration sites in the human genome. Thus, our results indicate that the adult heart contains a pool of resident stem cells that regulate cardiac homeostasis and repair.
  Proceedings of the National Academy of Sciences 10/2009; 106(40):17169-74. · 9.68 Impact Factor