Comparative Outcomes of Intravenous, Intranasal, and Intracerebroventricular Transplantation of Human Neural Stem Cells in Mice Model of Ischemic Stroke

BACKGROUND: Transplantation of neural stem cells improves ischemic stroke outcomes in rodent models and is currently in the clinical test stage. However, the optimal delivery route to achieve improved efficacy remains undetermined. OBJECTIVE: This study aims to evaluate three more clinically feasible delivery routes: intravenous (IV), intranasal (IN), and intracerebroventricular (ICV). We compared the therapeutic efficacies of the three routes of transplanting human neural stem cells (hNSCs) into mice with permanent middle cerebral artery obstruction (pMCAO). METHODS: Behavioral tests and cresyl violet staining were used to evaluate the therapeutic efficacies of functional recovery and lesion volumes. The expression of proinflammatory cytokines and neurotrophic factors was measured by real-time PCR. The distribution and differentiation of hNSCs were determined by immunofluorescence staining. The effect on endogenous neurogenesis and astrocyte function were determined by immunofluorescence staining and western blot. RESULTS: hNSC transplantation using the three routes improved behavioral outcomes and reduced lesion volumes; IV transplantation of hNSCs results in earlier efficacy and improves the inflammatory microenvironment. The long-term distribution and differentiation of transplanted hNSCs in the peri-infarct areas can only be evaluated using ICV delivery. IV and ICV transplantation of hNSCs promote neurogenesis and modulate the dual function of astrocytes in the peri-infarct areas. CONCLUSION: IV and IN delivery is suitable for repeated administration of hNSCs to achieve improved prognosis. Comparatively, ICV transplantation provides long-term efficacy at lower doses and fewer administration times.