The GLP1R Agonist Semaglutide Inhibits Reactive Astrocytes and Enhances the Efficacy of Neural Stem Cell Transplantation Therapy in Parkinson's Disease Mice

Cell transplantation offers a promising approach for treating Parkinson's disease (PD), but the limited survival of transplanted cells remains a major challenge. Reactive astrocytes, abundant in PD brains, may exacerbate this issue. GLP1R agonists, like semaglutide, are shown to inhibit reactive astrocytes in PD models. This study explores whether semaglutide could enhance the survival of transplanted neural stem cells (NSCs) in PD treatment. Six-hydroxydopamine-induced PD mouse models are used, with midbrain-derived NSCs transplanted into the lesioned striatum. Semaglutide is administered every other day for four weeks. In vivo imaging tracks the survival and distribution of DiD-labeled NSCs, while differentiation and astrocyte phenotypic changes are examined. Results show that semaglutide combined with NSC transplantation improves motor function. The mean fluorescence photon flux of mice transplanted with DiD-labeled NSCs alone is 0.8192 × 10^-11, compared to 3.258 × 10^-11 in those receiving both semaglutide and NSCs. Additionally, semaglutide reduces C3⁺ reactive astrocytes (previously A1 reactive astrocytes) in the striatum. Co-culture experiments indicate that C3⁺ reactive astrocytes hinder NSCs differentiation. RNA-seq reveals enriched inflammatory factors in C3⁺ astrocytes. Semaglutide combined with NSCs transplantation may enhance PD treatment partly by inhibiting C3⁺ reactive astrocytes and promoting the survival and differentiation of transplanted cells.