Some forms of therapy can be delivered to the brain by being sprayed into the nasal cavity; viral vectors, for examples, and extracellular vesicles in the example here. Extracellular vesicles carry much of the signaling that passes between cells, and can be harvested from cell culture populations of stem cells. The benefits of first generation stem cell therapies are thought to result from the signaling produced by the transplanted cells in the short time before they die, and thus the field is shifting towards the use of stem cell derived vesicles instead. Researchers here show that stem cell derived extracellular vesicles delivered via nasal spray can beneficially dampen inflammation in microglia, innate immune cells of the brain. Overly inflammatory microglia are implicated in the development of neurodegenerative conditions such as Alzheimer's disease.
As current treatments for Alzheimer's disease (AD) lack disease-modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti-inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC-NSC-EVs in 3-month-old 5xFAD mice.
IN administered hiPSC-NSC-EVs incorporated into microglia, including plaque-associated microglia, and encountered astrocytes in the brain. Single-cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease-associated microglia, NLRP3-inflammasome, and IFN-1 signalling displayed reduced expression in microglia. Astrocytes also displayed reduced expression of genes linked to IFN-1 and interleukin-6 signalling. Furthermore, the modulatory effects of hiPSC-NSC-EVs on microglia in the hippocampus persisted 2 months post-EV treatment without impacting their phagocytosis function. The extent of astrocyte hypertrophy, amyloid-beta plaques, and p-tau were also reduced in the hippocampus. Such modulatory effects of hiPSC-NSC-EVs also led to better cognitive and mood function.
Thus, early hiPSC-NSC-EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid-beta plaque load, and p-tau. These results reflect the first demonstration of the efficacy of hiPSC-NSC-EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.
Link: https://doi.org/10.1002/jev2.12519
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