Abstract 355: CardioClusters: Harnessing the Power of Multi-lineage Cardiac Stem Cells

Abstract

Existing approaches to modify stem cells for myocardial regeneration desperately need innovative solutions that enhance cell engraftment and persistence. Although this deficiency has been attacked through combinatorial stem cell delivery, there is no evidence that these stem cell injections provide for direct cellular crosstalk to promote stem cell survival and proliferation. Therefore, we created a CardioCluster, a 3D microenvironment consisting of three defined cell populations from the human heart: c-kit + cardiac progenitor cells (CPCs), CD90 + /CD105 + mesenchymal stem cells (MSCs) and CD133 + endothelial progenitor cells (EPCs). The size of the CardioCluster can be controlled by the quantity of cells used to create the cluster, allowing them to be infused into the heart without being reduced to single cell suspensions as is the case for cardiosphere-derived cells where the structural and cell-cell contact information is lost when delivered. Unlike cardiospheres, these cardiac cells are combined into a rationally designed cluster with MSCs and CPCs in the central core and EPCs forming the outer layer. EPCs play a vital role in forming neovasculature that will connect the CardioClusters to living heart tissue not damaged by ischemia and allow for revascularization of the damaged myocardium. In vitro we have shown that EPCs are better able to form tubular networks on matrigel-coated plates compared to either CPCs or MSCs. MSCs reinforce the 3D structure by releasing growth factors that attract and maintain cells within the cluster, as well as release immunomodulatory signaling factors. Upon induction of an oxidative stress by hydrogen peroxide CardioClusters show improved cell survival with a lower percentage of apoptotic and/or necrotic cell populations compared to the three populations individually. Upon myocardial injection CardioClusters have been shown to maintain their 3D structural integrity. Future directions will be to assess long-term engraftment and regenerative potential in a mouse model of myocardial infarction.