Grafting of electrically stimulated subventricular neural stem cells embedded in a nutritional hydrogel into the stroke cavity improved cell survival and behavioural recovery in mice

Abstract

Abstract The major aim of stroke therapy is to stimulate brain repair and improve behavioral recuperation after cerebral ischemia. One option is to stimulate endogenous neurogenesis in the sub-ventricular zone (SVZ) and direct the newly formed neurons to the damaged area. However, only a small percentage of these neurons survive and, of those that do, many will not reach the damaged area possibly because the corpus callosum impedes the migration of SVZ-derived stem cells into the lesioned cortex. A second major obstacle to stem cell therapy is the strong inflammatory reaction induced by cerebral ischemia whereby the associated phagocytic activity of brain macrophages removes both therapeutic cells and/or cell-based drug carriers. In order to address these issues, neurogenesis was electrically stimulated in the SVZ followed by isolation of proliferating cells including the newly formed neurons which were subsequently mixed with a nutritional hydrogel. This mixture was then transferred to the stroke cavity of day 14 post-stroke mice. We found that the treated animals showed improved performance with behavioral tests including novel object, open field, hole board, grooming, and „time-to-feel’ the adhesive tape. Furthermore, immunostaining showed that the stem cell markers nestin and Mash1, found in stimulated SVZ, survived for 2 weeks following transplantation. These results clearly indicate that transplantation of committed SVZ stem cells combined with a protective nutritional gel, directly into the infarct cavity after the peak of stroke-induced neuroinflammation, represents a feasible approach to improve neurorestoration after cerebral ischemia.