Intranasal Human NSC-Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS-STING...

Area of Science:

• Neuroscience
• Immunology
• Gerontology

Background:

• Neuroinflammaging, characterized by chronic hippocampal inflammation, contributes to age-related cognitive decline.
• This inflammation involves the activation of NLRP3 inflammasomes and the cGAS-STING-IFN-1 pathway.
• Extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) possess therapeutic potential for neuroinflammation.

Purpose of the Study:

• To investigate the effects of intranasal hiPSC-NSC-EVs on neuroinflammaging in late middle-aged mice.
• To determine if hiPSC-NSC-EVs can alleviate hippocampal inflammation and improve cognitive function in aging.

Main Methods:

• Administration of two intranasal doses of hiPSC-NSC-EVs to 18-month-old male and female mice.
• Analysis of hippocampal tissue for markers of inflammation, oxidative stress, and mitochondrial integrity.
• In vitro assays with RAW cells and single-cell RNA sequencing of microglia post-treatment.

Main Results:

• hiPSC-NSC-EVs treatment reduced astrocyte hypertrophy, microglial clusters, and oxidative stress in the hippocampus.
• Therapy decreased NLRP3 inflammasome, p38 MAPK, cGAS-STING-IFN-1, and JAK-STAT pathway activation.
• Specific miRNAs (miRNA-30e-3p and miRNA-181a-5p) within hiPSC-NSC-EVs were identified as key inhibitors.
• Single-cell RNA sequencing revealed hiPSC-NSC-EVs shifted microglia towards an anti-inflammatory and metabolically efficient state.
• Improved cognitive and memory functions were observed in treated animals.

Conclusions:

• Intranasal hiPSC-NSC-EVs therapy effectively mitigates neuroinflammaging in the aging hippocampus.
• The treatment enhances mitochondrial function and reduces pro-inflammatory signaling in microglia.
• This therapeutic approach offers a promising strategy for improving brain function in old age.