The heart is a self-renewing organ characterized by resident cardiac stem cells (CSCs) and early committed cells (ECCs) stored in niches. This novel view of the heart raises the possibility that myocardial aging occurs as a result of a progressive increase in the number of CSCs-ECCs permanently withdrawn from the cell cycle in spite of an increase in apoptosis of these cells. In fact, the rate of accumulation of old CSCs-ECCs might be greater than the rate of their death leading to the formation of senescent niches and organ aging. The old paradigm that apoptosis of CSCs-ECCs and myocytes is bad for the heart is challenged and a new paradigm is introduced. Apoptosis of non-dividing CSCs- ECCs and hypertrophied senescent myocytes is proposed here as a beneficial healthy process that preserves the youth of the heart and, thereby, the youth of its parenchymal cells. Conversely, resistance to apoptosis accelerates cardiac aging and the onset of ventricular dysfunction. With age, CSCs-ECCs clustered in the niches may become less susceptible to apoptosis, less prone to re-enter the cell cycle and less capable of leaving the niches, growing and differentiating. Therefore, the physiologic turnover of myocytes is impaired and old less efficient cells accumulate in the ventricle. In the young heart, a single CSC may sustain, when the need arises, the entire replacement of cells dictated by the high functional requirements of the heart; this mechanism corresponds to the model of clonal stability of growth. This may not be the case in the old heart in which several CSCs may be concurrently involved in the replacement of dying cells; this mechanism corresponds to the model of clonal succession of growth. Three animal models will be used: the telomerase null (Terc-/-) mouse, the W/WV mouse and the super p53 mouse. The Terc-/- mouse has a cardiac phenotype that is consistent with precocious aging of CSCs, myocytes and heart failure. The W/WV mouse has a mutation of the c-kit receptor with loss of stem cell function, accelerated CSC-ECC and myocyte aging. In contrast, the super p53 mouse has an enhanced expression of wild-type p53 in the cells; p53 is not constitutively activated but, upon stimulation, leads to an amplified p53 response. The Terc-/- mouse and the W/WV mouse will allow us to determine whether defects in the growth of CSCs-ECCs (Terc-/-) and impaired CSC-ECC function (W/WV) result in the accumulation of old non-dividing primitive cells within the niches and senescent myocytes in the ventricles. The number of apoptosis-resistant CSCs-ECCs in the niches is anticipated to increase resulting in an accelerated formation of senescent niches and precocious shift from clonal stability to clonal succession of myocardial turnover. Conversely, the p53 mouse may have an enhanced turnover of CSCs-ECCs as a result of potentiation of their death and longer preservation of clonal stability versus clonal succession of myocardial growth. Similarly, the ameliorated regeneration of myocytes due to the enhanced apoptosis may delay the accumulation of senescent cells and, therefore, the onset of cardiac aging and dysfunction. Ultimately, lifespan may be increased in the super p53 mouse. This work will advance our understanding of the biology of aging and heart failure. ? ?
| Kannappan, Ramaswamy; Matsuda, Alex; Ferreira-Martins, João et al. (2017) p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo. EBioMedicine 16:224-237 |
| Leri, Annarosa; Rota, Marcello; Pasqualini, Francesco S et al. (2015) Origin of cardiomyocytes in the adult heart. Circ Res 116:150-66 |
| Iso, Yoshitaka; Rao, Krithika S; Poole, Charla N et al. (2014) Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction. Stem Cells 32:674-83 |
| D'Amario, Domenico; Leone, Antonio M; Iaconelli, Antonio et al. (2014) Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery. Circulation 129:157-72 |
| Leri, Annarosa; Rota, Marcello; Hosoda, Toru et al. (2014) Cardiac stem cell niches. Stem Cell Res 13:631-46 |
| Sanada, Fumihiro; Kim, Junghyun; Czarna, Anna et al. (2014) c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res 114:41-55 |
| Rota, Marcello; Leri, Annarosa; Anversa, Piero (2014) Human heart failure: is cell therapy a valid option? Biochem Pharmacol 88:129-38 |
| Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2014) Response to letter regarding article ""Inositol 1,4,5-trisphosphate receptors and human left ventricular myocytes"". Circulation 129:e510-1 |
| Anversa, Piero; Leri, Annarosa (2013) Innate regeneration in the aging heart: healing from within. Mayo Clin Proc 88:871-83 |
| Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2013) Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circulation 128:1286-97 |
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