Abstract 16273: Cardiospheres Recapitulate a Niche-Like Microenvironment Rich in Stemness and Cell-Matrix Interactions, Rationalizing Their Enhanced Functional Potency for Myocardial Repair
Aims: Cardiac stem cells are promising candidates for use in myocardial regenerative therapy. We compared the functional effects and phenotypes of cardiac-derived cells cultured as three-dimensional cardiospheres, as opposed to monolayers or dispersed single cells
Methods and Results: Human endomyocardial biopsies yielded spontaneous outgrowths of cardiac stem cells and supporting cells, which were grown as cardiospheres or in traditional monolayers. Cardiospheres self-assembled into stem cell niche-like structures characterized by a central core of c-kit+ cells surrounding by collagen IV and CD105+ supporting cells. Furthermore, cardiospheres exhibited greater proportions of c-kit+ cells (p<0.01) and up-regulated expression of SOX2 and Nanog relative to monolayers (p<0.01). Quantitative RT-PCR and immunostaining revealed enhanced expression of stem cell-relevant factors and adhesion/ extracellular-matrix molecules (ECM) in cardiospheres, including IGF-1, HDAC2, Tert, integrin-α2, laminin-β1 and MMPs. Injection of cardiospheres into SCID mouse hearts after coronary ligation disproportionately improved cell engraftment (Figure A) and myocardial function (Figure B), relative to monolayer-cultured cells. Dissociation of cardiospheres into single cells decreased the presence of ECM and adhesion molecules and undermined resistance to oxidative stress, completely negating the improved cell engraftment and functional benefit in vivo (Figure A and B).
Conclusions: Growth of cardiac-derived cells as cardiospheres mimics stem cell niche properties, with enhanced “stemness” and expression of ECM and adhesion molecules. These changes underlie an increase in cell survival and more potent augmentation of global function following implantation into the infarcted heart, relative to dissociated cells from the same source tissue.
- © 2010 by American Heart Association, Inc.