The promise of regenerative stem cell therapies are not likely to achieve clinical translation without the identification of an abundant, readily available, non-controversial source of cells. Our lab has identified adipose tissue as such a candidate cell source. A population of cells from human adipose tissue displays multi-lineage developmental plasticity in vitro, including adipogenic, osteogenic, chondrogenic, neurogenic and myogenic potential. Adipose tissue, more than any other primary human adult tissue, has the potential to enable the translation of autologous cell-based paradigms to the clinic because of its abundance, ease of harvest, appeal, expendability, and non-controversial nature. This proposal will specifically explore the cardiomyogenic potential of human adipo-derived cells within three settings: 1) in vitro, 2) in uninjured myocardium, and 3) in infarcted myocardium. This will be done with a multidisciplinary team consisting of clinicians, researchers and engineers that span the fields of plastic surgery, radiology, cardiac physiology, cell and molecular biology and biomedical engineering. The in vivo studies will employ a mouse model of left ventricular remodeling secondary to reperfused myocardial infarction (MI) that has already been established at UVA by the co-investigator. Using this model, the effects of cell transplantation on both global and regional myocardial function after MI will be assessed in a serial, non-invasive manner using state-of-the-art magnetic resonance imaging (MRI) coupled with advanced techniques of myocardial tagging. The specific aims of this proposal are: 1) Explore and characterize the cardiomyogenic potential of human adipo-derived cells (hADCs) in the in vitro setting. The cells have previously been shown to differentiate along the (skeletal) myogenic lineage. The potential for targeted induction along the cardiomyogenic lineage will be explored using co-culture techniques in conjunction with bioactive factors implicated in cardiogenic commitment and differentiation. 2) Explore the plasticity of hADCs after implantation into a normal myocardial milieu in a murine model. The microenvironment is known to significantly influence cell growth and differentiation. Therefore, the fate of hADCs after intramyocardial injection will be evaluated. 3) Explore the plasticity of hADCs after implantation into an infarcted myocardial milieu in vivo using a murine model. Signals released by damaged tissues have been shown to influence the growth, migration and differentiation of cells in vivo. This specific aim will determine whether intramyocardial injection of hADCs can reduce LV remodeling and improve cardiac function in a murine model of chronic myocardial infarction.

R21HL072141

2002-09-30

2007-07-31