This project has three principal goals: 1. The recognition of the role that stem cell surface antigens have in conditioning the growth and differentiation of cardiac stem cells (CSCs) in myocardial cell lineages; 2. The demonstration that age leads to a downregulation of the hepatocyte growth factor (HGF)-cMet and insulin-like growth factor-1 (IGF-1)-IGF-1 receptor (IGF-1R) systems, and to an upregulation of the renin-angiotensin system (RAS) in CSCs and early committed cells; and 3. The identification of an age-dependent increase in the local RAS, which mediates the formation of reactive oxygen species (ROS), triggering apoptotic and necrotic death of CSCs, progenitors and precursors. Point 1 aims at the characterization of the classes of CSCs regulating the physiologic turnover of myocardial cells in the adult normal heart. This information is considered critical for the elucidation of the potential mechanisms of cardiac repair in disease states. Point 2 raises the possibility that attenuation of the HGF-c-Met system with age negatively interferes with the migration of CSCs from the storage areas to the injured sites of ventricular myocardium, limiting their activation and growth. Reduction of cell turnover results in accumulation of old cardiac cells with defective function. Similarly, the IGF-I-IGF-I R system might be downregulated in aging CSCs and this could affect cell replication, differentiation and survival, contributing to the development of the aging myopathy. Point 3 emphasizes the effects of oxidative damage induced by an upregulation of the local RAS not adequately counteracted by the IGF-I-IGF-1R system in the old heart. Low levels of oxidative challenge initiate apoptosis and high levels promote necrosis. Death of CSCs and early committed cells may result in the loss of the growth reserve of the aging myocardium. Senescent myocytes, coronary arterioles and capillary structures could die and the architecture of the ventricular wall may assume pathologic characteristics. These might include mural thinning, cavitary dilation, poor tissue perfusion, cardiac dysfunction and, ultimately, terminal failure and death. Thus, the hypothesis is advanced that CSC aging occurs and involves downregulation of growth factor receptor systems favoring locomotion, growth and differentiation. Conversely, inhibitors of the cell cycle and marker of cellular senescence increase in combination with oxidative DNA damage, potentiating the endogenous cell death pathway.
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| Anversa, Piero; Leri, Annarosa; Kajstura, Jan (2012) Biased DNA segregation during stem cell division. Circ Res 110:1403-7 |
| Ferreira-Martins, João; Ogórek, Barbara; Cappetta, Donato et al. (2012) Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells. Circ Res 110:701-15 |
| Kajstura, Jan; Rota, Marcello; Hosoda, Toru et al. (2012) Response to Bergmann et al: Carbon 14 Birth Dating of Human Cardiomyocytes. Circ Res 110:e19-e21 |
| Kajstura, Jan; Rota, Marcello; Cappetta, Donato et al. (2012) Cardiomyogenesis in the aging and failing human heart. Circulation 126:1869-81 |
| Kajstura, Jan; Bai, Yingnan; Cappetta, Donato et al. (2012) Tracking chromatid segregation to identify human cardiac stem cells that regenerate extensively the infarcted myocardium. Circ Res 111:894-906 |
| Goichberg, Polina; Bai, Yingnan; D'Amario, Domenico et al. (2011) The ephrin A1-EphA2 system promotes cardiac stem cell migration after infarction. Circ Res 108:1071-83 |
| Hosoda, Toru; Zheng, Hanqiao; Cabral-da-Silva, Mauricio et al. (2011) Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation 123:1287-96 |
| Leri, Annarosa; Kajstura, Jan; Anversa, Piero (2011) Mechanisms of myocardial regeneration. Trends Cardiovasc Med 21:52-8 |
| D'Amario, Domenico; Fiorini, Claudia; Campbell, Patricia M et al. (2011) Functionally competent cardiac stem cells can be isolated from endomyocardial biopsies of patients with advanced cardiomyopathies. Circ Res 108:857-61 |
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