Although several laboratories have identified cardiac progenitor cells (CPCs), the controversy concerning myocyte regeneration in the adult heart has not been resolved. Similarly, the plasticity of bone marrow derived progenitor cells (BMPCs) and their ability to acquire the myocyte lineage and regenerate dead myocardium has been challenged. Therefore, one of the major objectives of this application is to determine by a novel approach that involves genetic tagging and clonal marking, whether c-kit-positive BMPCs and CPCs acquire a cardiac phenotype and give rise to a large number of myocyte-committed progeny. The therapeutic efficacy of these two classes of progenitor cells for acute and chronic ischemic heart failure depends on their ability (a) to survive in the hostile milieu of the damaged heart, (b) to engraft within the myocardium, and (c) to grow and differentiate. BMPCs may have a growth potential, which is superior to 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 lose in part their capability of dividing through alterations of the telomere-telomerase system, premature cellular senescence, and apoptosis. Similarly, 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 even after transdifferentiation a stronger regenerative capacity than CPCs representing the most appropriate cells for the damaged heart. With BMPCs, the newly formed myocytes appear to have fetal- neonatal properties and may not reach the adult phenotype, a problem that may not affect the commitment of CPCs. Relative hypoxia at the1 border and infarct may modulate the Notch pathway, and prolonged Notch activation may inhibit downregulation of Nkx2.5 and, thereby, the transition from early to late myocyte differentiation. Notch may repress transcription of GATA4, which could be critical for irreversible myocyte commitment. This behavior conforms to a model of differentiation delay in which the persistence of Notch opposes the progression of maturation. Ultimately, the proposed work addresses the question whether BMPCs are superior, equal, or inferior to CPCs for the regeneration of cardiomyocytes and coronary vessels in ischemic heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065577-08
Application #
7780449
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2000-09-01
Project End
2012-11-30
Budget Start
2010-03-01
Budget End
2011-11-30
Support Year
8
Fiscal Year
2010
Total Cost
$371,250
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
Leri, Annarosa; Anversa, Piero (2013) Stem cells and myocardial regeneration: cooperation wins over competition. Circulation 127:165-8
Schoenfeld, Matthew; Frishman, William H; Leri, Annarosa et al. (2013) The existence of myocardial repair: mechanistic insights and enhancements. Cardiol Rev 21:111-20

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