Cardiomyocytes in the adult mammal exhibit little if any capacity to undergo cell division. Consequently cardiomyocyte loss due to injury or disease is irreversible. The ability to utilize intracardiac grafting as a means to replace scarred, nonfunctional myocardium in a diseased heart with viable, functional cardiomyocytes would have significant therapeutic value. Preliminary experiments from this laboratory have established the feasibility of intracardiac grafting using a variety of cell types. These studies demonstrate that the myocardium can serve as a stable platform for cells which have been manipulated in vitro. In this application we propose to extend these findings in an effort to develop models which test the feasibility of utilizing intracardiac grafting to effect myocardial replacement. We propose five Specific Aim with the goal of developing models which test the feasibility of intracardiac grafting as a means to effect myocardial repair. They are: 1: Intracardiac grafting in the mouse heart with fetal ventricular cardiomyocytes derived from mice expressing a cytological """"""""tag"""""""" in the myocardium. 2: Intracardiac grafting in the mouse heart with cardiomyocytes derived from murine embryonic stem (ES) cells. 3: Intracardiac grafting in the mouse heart with genetically modified skeletal myoblasts. 4: Intracardiac grafting in the infarcted rat heart with fetal ventricular cardiomyocytes derived from mice expressing a cytological """"""""tag"""""""" in the myocardium. 5: Intracardiac grafting in the dystrophic canine heart using dystrophin expressing fetal cardiomyocytes. Together, the proposed experiments should enable us to ascertain the feasibility of employing intracardiac graftings as a means to repair damaged or diseased myocardium.
Specific Aims 4 and 5 have the advantag that functional analyses of graft-bearing canine hearts are readily accomplished using established in house methodologies.
|Klug, M G; Soonpaa, M H; Koh, G Y et al. (1996) Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest 98:216-24|