Cellular therapy to treat heart failure is an ongoing focus of intense research, but with limited progress due to limitations in engraftment and persistence of injected cells. Engineered augmentation of established cellular effectors overcomes impediments, enhancing reparative activity. Such ‘next generation’ implementation includes delivery of combinatorial cell populations working together synergistically to improve heart function following injury. Concurrent isolation and expansion of 3 distinct cardiac-derived interstitial cell types from human heart tissue prompted design of a 3D structure that maximizes cellular interaction, allows for defined cell ratios, controls size, enables injectability, and minimizes cell loss. Here we describe a method wherein, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and c-Kit+ cardiac interstitial cells (cCICs) when cultured together spontaneously form scaffold-free 3D microenvironments we have termed 'CardioClusters'.