Mesenchymal stem cells and their derived extracellular vesicles (MSC-EVs) have been previously reported to regulate inflammation in Alzheimer’s disease (AD). MSC-EVs were administered either intravenously or directly into the fluid within the chambers of the brain (cerebral ventricles) over an extended period of weeks or months. However, results from a new study done on mice revealed that administration of the MSC-EVs through intranasal delivery reduced inflammation over a much shorter period of time, and also triggered actions that guard neurons against further degenerative effects.

The study, “Intranasal delivery of mesenchymal stem cell‐derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer’s disease,” published in Stem Cells Translational Medicine, is led by Silvia Coco, PhD, at the University of Milano-Bicocca in Italy.

“The critical role of neuroinflammation in favoring and accelerating the pathogenic process in AD increased the need to target the cerebral innate immune cells as a potential therapeutic strategy to slow down the disease progression. In this scenario, mesenchymal stem cells (MSCs) have risen considerable interest thanks to their immunomodulatory properties, which have been largely ascribed to the release of extracellular vesicles (EVs), namely exosomes and microvesicles,” the researchers wrote.

In earlier studies, MSC-EVs were administered either intravenously or directly into the fluid within the chambers of the brain (cerebral ventricles) over an extended period of weeks or months, but Coco and her team decided to take a different approach. “We believed that the possibility to administer MSC-EVs through a noninvasive route and the demonstration of their anti-inflammatory efficacy might accelerate the chance of exploiting MSC-EVs to treat Alzheimer’s disease,” noted Coco.

The team conducted their study both in vitro and in vivo, by collecting MSCs from the bone marrow of healthy human donors and preconditioning them with cytokines, to increase the MSCs’ anti-inflammatory abilities and boost their release of EVs.

For the in vitro segment of their study, the team added the resulting MSC-EVs to microglia—cells that mediate immune responses in the central nervous system—isolated from newborn C57BL/6 mice. (The applications were done at intervals of two and 24 hours. The results were then analyzed 48 hours after the final application.)

For the in vivo segment of the study, the team administered two doses of MSC-EVs to a group of seven-month-old female mice with AD. The applications were done through the nasal passages, with the second dose occurring just 18 hours after the first. When they assessed the results 21 days later, they found that the MSC-EVs had dampened the activation of the microglia cells in the mice brains and increased the density of dendritic spines.

“We believe that the striking aspect of our study resides in the fact that the observed effects were achieved by only two intranasal injections of MSC-EVs delivered just hours apart,” Coco stated. “This might possibly have occurred because EVs delivered intranasally could reach higher levels than those delivered by other methods.”

Their results strengthen the idea that mechanisms of action other than the removal of amyloid plaques from the brain should be considered when treating AD. This study opens the door for future studies that might lead the way to a cure for AD.

“The results from this study present an opportunity for potentially effective therapies to be tested by human pilot clinical trials. This work is worthy to progress forward,” said Anthony Atala, MD, editor-in-chief of Stem Cells Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.

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