Intranasal delivery of extracellular vesicles from stem cells reduces the activity of specific inflammatory pathways and lowers levels of key inflammatory proteins in the hippocampus of aged mice.
Mechanism
Synthesis from 1 study
Stem cell bubbles delivered through the nose enter brain immune cells and release tiny molecules that shut down two major inflammation switches. This stops the release of harmful chemicals that damage brain cells in aging, helping the brain function better.
Most probable mechanism
Tiny bubbles from stem cells, delivered through the nose, enter brain immune cells and release specific molecules that block two key inflammation systems. One molecule stops a protein called NLRP3 from forming a harmful complex, and another molecule stops a protein called STING from turning on a signal that produces inflammatory chemicals. This reduces the release of inflammatory substances that damage brain cells in aging.
hiPSC-NSC-EVs are taken up by microglia in the hippocampus after intranasal delivery
miR-30e-3p from EVs binds to the 3'UTR of NLRP3 mRNA, suppressing translation of NLRP3 protein
Reduced NLRP3 protein impairs assembly of the NLRP3-ASC-caspase-1 inflammasome complex
Inflammasome assembly failure prevents cleavage and activation of caspase-1
miR-181a-5p from EVs binds to STING mRNA, suppressing translation of STING protein
Reduced STING protein impairs its oligomerization and downstream phosphorylation of TBK1 and IRF3
Inactive IRF3 fails to drive transcription of IFN-α and other interferon-stimulated genes
Suppression of both pathways reduces secretion of IL-1β, IL-18, and IFN-α in the hippocampus
Less supported by current evidence, but not ruled out
The stem cell bubbles change the activity of brain immune cells, turning off genes that cause inflammation and turning on genes that help cells produce energy and stay healthy, which reduces overall brain inflammation.
hiPSC-NSC-EVs are internalized by microglia in the hippocampus
EV cargo induces widespread changes in microglial gene expression, suppressing proinflammatory pathways (TLR, MAPK, TNF, IL-17, NOD-like)
EV cargo enhances expression of genes involved in oxidative phosphorylation and cholesterol metabolism
Transcriptional reprogramming reduces microglial activation and disease-associated clustering
Shifted microglial phenotype reduces release of proinflammatory cytokines and oxidative stress markers
By lowering inflammation, the stem cell bubbles help brain cells repair their energy-producing parts, which reduces harmful byproducts and improves cell health.
Suppression of NLRP3 and cGAS-STING pathways reduces microglial ROS production and inflammatory cytokine release
Lower oxidative stress reduces damage to mitochondrial DNA and proteins
Expression of nuclear-encoded mitochondrial respiratory chain genes is restored
Improved electron transport chain function increases ATP synthesis and reduces mitochondrial ROS leakage
Evidence from Studies
Supporting (1)
Community contributions welcome
Intranasal Human NSC‐Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS‐STING Signalling, in Aged Hippocampus
Contradicting (0)
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