This project addresses the controversy on cardiomyogenesis of the adult mouse heart, and raises the unexplored possibility that the aging myopathy is dependent on alterations of cardiac stem cell (CSC) growth and differentiation. The major hypothesis to be tested is that myocardial aging is a stem cell disease and defects in CSC behavior determine the structural and physiological manifestations of the old heart. Cardiomyogenesis, mediated by CSC activation and lineage specification, may change dramatically during the lifespan of the mouse heart, and the phenotypic properties of aged CSCs may impact on the size, composition, and function of the derived progeny. Aged CSCs may form more fibroblasts and less myocytes than young CSCs, resulting in an impairment of myocyte relaxation and ventricular compliance, typical aspects of diastolic dysfunction and the cardiac senescent phenotype. However, a pool of young CSCs may persist in the old heart and could be implemented to rescue and, eventually, reverse the aging myopathy. To establish the cellular mechanisms involved in the maturation of the heart, tissue homeostasis in the adult organ, and myocardial aging, we will employ three distinct approaches, which are dependent on separate parameters: a) The average age of myocytes and non-myocytes will be determined by 14C thymidine birth dating of cardiac cells;b) The age distribution of myocytes and non-myocytes will be defined by a novel strategy based on age-structured cell populations;and c) The rate of formation of myocytes and nonmyocytes derived from commitment of CSCs will be evaluated by a model of hierarchically organized cells. These 3 sets of information will offer a "redundant" perspective of the cellular dynamics of the mouse heart.

Public Health Relevance

This research raises the possibility that the aging myopathy is dictated by defects in the function of resident CSCs and that strategies may be developed to implement stem cell therapy to rescue and eventually reverse myocardial aging and diastolic and systolic heart failure in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG043353-02
Application #
8588877
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$368,333
Indirect Cost
$159,597
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Goichberg, Polina; Chang, Jerway; Liao, Ronglih et al. (2014) Cardiac stem cells: biology and clinical applications. Antioxid Redox Signal 21:2002-17
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
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
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
Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, Joao et al. (2013) Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circulation 128:1286-97
Goichberg, Polina; Kannappan, Ramaswamy; Cimini, Maria et al. (2013) Age-associated defects in EphA2 signaling impair the migration of human cardiac progenitor cells. Circulation 128:2211-23
Leri, Annarosa; Anversa, Piero (2013) Stem cells and myocardial regeneration: cooperation wins over competition. Circulation 127:165-8

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