Abstract
Cell transplantation for therapeutic neovascularization holds great promise for treating ischemic diseases. However, following injections, retention of transplanted cells in engrafted areas remains problematic, and can be deleterious to cell-transplantation therapy. Additionally, reactive oxygen species (ROSs) are generated during tissue ischemia, which may disrupt cellular function of the engrafted cells via oxidation of major cellular macromolecules, such as lipid, DNA and protein. To enhance the cell retention and the subsequent therapeutic benefits, three-dimensional aggregates of human umbilical vein endothelial cells (HUVECs) and cord-blood mesenchymal stem cells (cbMSCs) that had been reported in our previous studies were concurrently delivered with an antioxidant N-acetylcysteine (NAC) for the treatment of ischemic disease. The results of in vitro studies demonstrated that NAC can effectively reduce the environmental oxidative stress and improve the cell adhesion ability. Transplantation of HUVEC/cbMSC aggregates with NAC into a mouse model of an ischemic limb significantly reduced regional oxidative stress, promoted formation of functional vessels, improved limb blood perfusion, and attenuated muscle atrophy and bone losses, thereby rescuing tissue degeneration. Notably, the retention of engrafted cells and their therapeutic efficacy were significantly improved by the concurrent delivery of NAC. These analytical results demonstrate that by co-delivery with antioxidant NAC, the potential of HUVEC/cbMSC aggregates for therapeutic neovascularization can be markedly enhanced.