Intravenously injected hPSC-derived pericytes for Alzheimer disease: Neuroprotection and vascular repair via extracellular vesicles.

Intravenously injected human pluripotent stem cell (hPSC)-derived pericytes (PCs) and their extracellular vesicles (EVs) represent promising therapeutic strategies for neurological diseases. Our study aimed to investigate the effects and mechanisms of intravenous transplantation for treating Alzheimer disease (AD), with a focus on elucidating the critical role of EV-related mechanisms. We generated PCs (hPSC-CNC PCs) from hPSC-derived cranial neural crest (CNC) and employed 12-month-old 5xFAD mice as an advanced stage AD model. We investigated memory function, intracerebral β-amyloid (Aβ) deposition, blood-brain barrier (BBB) permeability, neuronal morphology, and associated protein expressions in mice to determine the therapeutic effects of intravenous administration of hPSC-CNC PCs or EVs. miRNA sequencing was conducted to identify potential downstream pathways. We found that intravenous administration of hPSC-CNC PCs improved memory function of aged AD mice, concurrently reducing pathological deposits and BBB leakage and enhancing neurofunctional outcomes via EVs. Furthermore, miRNA-486-5p in EVs might promote neurovascular repair through various mechanisms. Our results demonstrated that EVs from hPSC-CNC PCs exert protective effects against AD.