Researchers have discovered that extracellular vesicles (EVs) derived from the nasal mucosa provide significant regenerative benefits to tissues throughout the body, including the brain.
A very regenerative tissue
Previous work involving the transection of sizable portions of the nasal mucosa has found that this tissue grows back quickly and without scarring, even in older people [1], signifying that the tissue has intrinsic regenerative properties that persist despite aging. These researchers hypothesized that extracellular vesicles (EVs), which cells use to send proteins, RNA, and DNA to one another [2] and are a common subject of aging research, may be a key part of this ability.
However, the effects of EVs from regenerative tissues on entirely different, far less regenerative, tissues are little explored. Therefore, these researchers decided to take a broad look at mice injected with human-derived nasal mucosa EVs, with a focus on multiple crucial organs including the brain.
Overall benefits
The experimenters began by introducing human nasal mucosa EVs (nmEVs) into the tail veins of 20-month-old mice twice weekly for two months, assessing their physical performance every two weeks. The researchers observed no toxic effects from this treatment; instead, the treated mice had healthier fur, more body weight, stronger grips, and better balance on a rotating rod compared to a similarly aged control group.
Basic biomarker tests also suggested that the treated animals were in better health and more like younger animals: albumin was higher, while uric acid, aspartate aminotransferase, and blood lactate were lower than the control group. There were also improvements in bone health: while mice lose bone volume and density with age, both of these metrics was substantially improved in the treatment group.
There were improvements in memory as well. The treated mice performed much better on the Morris water maze test, with results approximating those of much younger mice, and they expressed significantly less inflammatory and senescence-related compounds along with more compounds related to neuroplasticity and the generation of axons.
Benefits for the brain
The researchers sequenced the RNA of individual nuclei derived from ten different cell types from the hippocampus, including types of glia and neurons. Compared to the control group, the treatment group experienced a marked shift in cell types, with a significant increase in neurons and a related decrease in glial cells. Examining the cells’ phases, the researchers found that the cells of the treated mice were proliferating more rapidly. Overall, the researchers hold that “systemic administration of nmEVs appears to preserve a more balanced neuro–glial composition in the aged hippocampus.”
An even closer look found very particular shifts. While glial cells were generally decreased in the treatment group, one particular type of astrocyte was markedly increased. These cells were found to express genes that relate to the circadian rhythm along with several pathways related to neuronal function and regulation. The researchers hold that this remodeling is likely to be neuroprotective.
Similarly, two types of metabolically active inhibitory neurons suspected to be prone to inflammation were decreased, while another type of inhibitory neuron was increased. The increased type was also related to the circadian rhythm, and other upregulated pathways led the researchers to the idea that this upregulation may improve the integrity of the brain’s synapses.
The most upregulated population, however, was a group of excitatory neurons. These neurons were found to be strongly enriched in both plasticity and metabolism, along with prevention of cellular death by apoptosis and more robust responses to DNA damage and oxidative stress. The researchers describe these neurons as “functionally enhanced” and suggest that this is why the mice’s cognitive abilities were improved.
Benefits for multiple other organs
Across multiple other tissue types, circadian rhythm-related genes were downregulated rather than upregulated, but the researchers suggested that this may be due to a reset of age-related circadian dysfunction. To test this hypothesis, they monitored the animals’ behavior during light and dark periods. In addition to running on a wheel for longer and being less prone to exhaustion, young mice and the treatment group had a distinct preference for running during the dark periods, while the untreated animals did not follow this rhythm.
Cellular senescence was downregulated as well, particularly in the spleen and heart. Certain immune pathways were also upregulated, but the researchers interpret this as being a beneficial immune reconfiguration rather than a sign of chronic inflammation. p53, which is overexpressed in aged tissues and is related to death by apoptosis, was also downregulated; further work established a strong link between p53 and the circadian rhythm at the cellular level, suggesting that this senescence-related factor affects that rhythm as well. The researchers also found that exposure to nmEVs reduces senescence in human bone marrow stem cells.
Overall, a detailed examination of protein expression, including senescence-related and inflammatory proteins, led the researchers to conclude that “nmEV treatment attenuated tissue fibrosis, reduced cellular senescence, and promoted an anti-inflammatory tissue environment.”
Sourcing autologous EVs, which are derived from the patient’s own cells, is usually difficult for older people. However, as the regenerative capacity of the nasal mucosa continues into old age, the researchers note that nmEVs can be repeatedly derived, making this tissue a significantly easier and most likely more potent source of these beneficial signals. Time, and clinical trials, will tell if nmEVs have the same effects in people as they do in mice, and more work needs to be done to determine which components of nmEVs are responsible for these effects.
Literature
[1] Agrawal, A. (Ed.). (2024). Skull Base Surgery-Pearls and Nuances: Pearls and Nuances. BoD–Books on Demand.
[2] Lei, Q., Gao, F., Liu, T., Ren, W., Chen, L., Cao, Y., … & Guo, A. Y. (2021). Extracellular vesicles deposit PCNA to rejuvenate aged bone marrow–derived mesenchymal stem cells and slow age-related degeneration. Science translational medicine, 13(578), eaaz8697.
