Abstract
ABSTRACT Myocardial infarction (MI) represents one of the major causes of morbidity and mortality worldwide. Following MI, cardiomyocytes undergo apoptosis due to the reduced or obstructed blood flow, thus leading to impaired cardiac functions. Stem cell transplantation is a promising therapeutic strategy for ischemic heart diseases; however, retention of the transplanted cells at the sites of the cell graft is frequently limited. In study I, we developed a methylcellulose hydrogel system to cultivate spherically-symmetric cell bodies with enriched endogenous extracellular matrices (ECM). The obtained cell bodies were transplanted into the skeletal muscle of rats via local injection. It was found that the cell aggregates can provide an adequate physical size to entrap into the muscular interstices and offer a favorable ECM environment to enhance retention of the transplanted cells at the sites of the cell graft. The obtained results indicated that the spherically-symmetric cell aggregates developed in the study may serve as a cell-delivery vehicle for therapeutic applications. Our previous study found that human amniotic-fluid stem cells (hAFSCs) are potential to differentiate into endothelial and cardiomyogenic lineages, thus being a suitable cell source for myocardial regeneration. In study II, we cultivated hAFSC bodies for cellular cardiomyoplasty in a rat MI model. Quantitative analyses revealed that, when compared to dissociated hAFSCs, the transplanted hAFSC bodies significantly promoted short-term cell retention and enhanced long-term engraftment, thus improving cardiac function. Rapid vascularization is essential for the success of treating ischemic tissues. The formation of mature and functional vascular networks requires the cooperation of endothelial cells (ECs) and perivascular cells. In study III, we fabricated core-shell cell bodies composed of cord-blood mesenchymal stem cells (cbMSCs) and human umbilical vascular ECs (HUVECs) for functional vasculogenesis. The in vitro Matrigel tube formation assay demonstrated the inherent abilities of cbMSC/HUVEC core-shell bodies in forming mature and stable tubular networks, showing that the cored cbMSCs can function as perivascular cells to stabilize the elongated vascular networks established by the shelled HUVECs. When embedded in Matrigel and implanted subcutaneously in nude mice, the cbMSC/HUVEC bodies could form visible blood-filled vessels within the matrix. In this study, we establish a new approach by using core-shell bodies of cbMSCs/HUVEVs for functional vascularization, providing a step forward in clinical applications. The vasculogenic cbMSC/HUVEC bodies were further xeno-transplanted in an experimentally-created MI rat model. Saline, HUVEC bodies and cbMSC bodies were used as controls. Four week after transplantation, rats received cbMSC/HUVEC bodies exhibited significant increased vessel densities and restored heart function. The study demonstrates a new concept of cellular cardiomyoplasy by implanting core-shell bodies of pericytes and ECs for vasculogenesis, thus enhancing blood perfusion and restoring impaired cardiac function