Intravenous and intranasal Muse cell administration delivers cognitive and histologic improvements in an Alzheimer’s disease model

Mesenchymal stromal cells (MSCs) contain several percentages of SSEA-3+ pluripotent-like Muse cells. We compared human bone marrow–derived Muse cells with MSC controls delivered intravenously (IV) or intranasally (IN) in 3 month old 5xFAD mice without immunosuppression. Light sheet imaging of mCherry labeled cells showed markedly greater brain retention of Muse cells at day 7 after IN delivery compared with MSCs. At 16 weeks, human cells, detected by anti–human mitochondria, human nuclear Ku80, and Alu ddPCR, were highly persistent in both Muse groups with neural and microglial marker expression. Muse treatment reduced amyloid β plaque burden and preserved pre-onset Y maze and Morris water maze performance through 16 weeks, with similar outcomes after IV and IN delivery. These findings support further evaluation of IN Muse cell delivery for AD cell therapy.