This application raises the possibility that the myocyte compartment of the embryonic, fetal and post-natal heart is generated by activation and lineage commitment of a pool of resident c-kit-positive cardiac progenitor cells (CPCs) which are clustered in niches within the primitive heart. Cardiac morphogenesis may be mediated by spontaneous calcium oscillations within CPCs which lead to cell growth and the acquisition of the myocyte phenotype. The possibility is raised that the fate of CPCs is regulated by transient changes in intracellular calcium which constitute the essential element of symmetric and asymmetric division of these primitive cells. Similarly, calcium oscillations condition the differentiation of CPCs into functionally competent myocytes which become electrically and mechanically excitable. To address these fundamental issues, two transgenic mouse models have been developed: one in which EGFP is under the control of the c-kit-promoter (c-kit-EGFP mouse) and the second in which EGFP expression is regulated by the cardiac specific ?-myosin heavy chain promoter (?MHC-EGFP mouse). The c-kit-EGFP mouse should allow us to identify the embryonic stages at which c-kit-positive-EGFP-positive CPCs appear in the forming heart, their anatomical distribution and developmental changes in prenatal and postnatal life. The ?MHC-EGFP mouse will permit us to define the localization and spatial distribution of forming myocytes postnatally and this information will be complemented with the data to be obtained in the c-kit-EGFP mouse. With these two models, the relationship between the generation of myocytes and the activation, commitment and differentiation of CPCs will be established. These studies will be integrated with the analysis of the electrophysiological, mechanical and calcium handling properties of CPCs and linearly related cells together with their pattern of growth and differentiation. Ultimately, the interdependence of cellular physiology and growth with calcium being the master regulatory system will be determined. Therefore, the role that intracardiac progenitor cells have in the developing heart will be characterized and this information may have important implications in the myocardial adaptations to ischemic and non-ischemic damage later in life.

Public Health Relevance

Determining whether a selective class of stem cells is implicated in cardiac development has consequences on our understanding of the formation of the heart and the mechanisms that regulate muscle contraction. This information is critical for the identification of the regenerative potential of the adult heart and its ability to react and repair in response to cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091021-04
Application #
8249041
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schramm, Charlene A
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$418,084
Indirect Cost
$170,584
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
Anversa, Piero; Kajstura, Jan; Rota, Marcello et al. (2013) Regenerating new heart with stem cells. J Clin Invest 123:62-70
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
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
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
Leri, Annarosa; Hosoda, Toru; Kajstura, Jan et al. (2011) Identification of a coronary stem cell in the human heart. J Mol Med (Berl) 89:947-59
Rota, Marcello (2010) SDF-1 axis and myocardial repair. Am J Physiol Heart Circ Physiol 299:H1307-8

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