The recognition that a pool of c-kit-positive cardiac progenitor cells (c-kit-CPCs) stored in niches is present in the adult mammalian heart has raised the question of their origin during embryonic and fetal development. To establish whether the heart develops as a self-autonomous organ regulated by the orderly organization and growth of resident c-kit-CPCs or originates from a continuous trafficking of undifferentiated cells from the bone marrow to the myocardium, a transgenic mouse model has been developed in which enhanced green fluorescent protein (EGFP) is placed under the control of the c-kit promoter (c-kit-EGFP mouse). The c-kit- EGFP mouse will allow us to characterize the timing and localization of c-kit-CPCs during embryonic and fetal myocardial growth and establish whether myocyte formation is modulated by the commitment and differentiation of c-kit-CPCs which acquire the myogenic fate. To achieve this goal, we will attempt to determine whether (a) the number of resident stem cells is controlled by activation of c-kit-CPCs within the cardiac niches, (b) growth signals lead to symmetric and asymmetric division of c-kit-CPCs, and (c) asymmetric division results in the generation of one undifferentiated daughter c-kit-CPC and one daughter lineage committed c-kit-CPC. While the undifferentiated c-kit-CPC establishes connections with the supporting cells within the niche (d) through the expression of junctional and adhesion proteins, the lineage committed cell (e) differentiates into working myocytes. The former repopulates the temporarily depleted niche and the latter increases the number of myocytes within the ventricle regulating the development of the adult heart phenotype. This work is critical for understanding whether c-kit-CPCs participate in the formation of the heart, and thereby condition cardiac homeostasis in adulthood and the development of the aging myopathy in the elderly. ? ? ?
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