Mesenchymal Stem Cells Improve Neurogenesis and Cognitive Function in Old Mice
The signaling produced by transplanted mesenchymal stem cells is well known to reduce the chronic inflammation that accompanies aging. This is a temporary effect, as the transplanted cells near all die rather than engraft, but it can lead to lasting improvement should the respite allow tissues to better maintain themselves for a time. Chronic inflammation is highly disruptive to tissue function, and drives the onset and progression of many age-related conditions. It is thus an important target for interventions aiming to reduce the burden of aging. Here, researchers show that mesenchymal stem cell therapy can improve neurogenesis and cognitive function in old mice, a good example of the way in which inflammation is relevant to degenerative aging.
Age-related decline in cognitive functions is associated with reduced hippocampal neurogenesis caused by changes in the systemic inflammatory milieu. Mesenchymal stem cells (MSC) are known for their immunomodulatory properties. Accordingly, MSC are a leading candidate for cell therapy and can be applied to alleviate inflammatory diseases as well as aging frailty via systemic delivery.
Akin to immune cells, MSC can also polarize into pro-inflammatory MSC (MSC1) and anti-inflammatory MSC (MSC2) following activation of Toll-like receptor 4 (TLR4) and TLR3, respectively. In the present study, we apply pituitary adenylate cyclase-activating peptide (PACAP) to polarize bone-marrow-derived MSC towards an MSC2 phenotype. Indeed, we found that polarized anti-inflammatory MSC were able to reduce the plasma levels of aging related chemokines in aged mice (18-months old) and increased hippocampal neurogenesis following systemic administration.
Similarly, aged mice treated with polarized MSC displayed improved cognitive function in the Morris water maze and Y-maze assays compared with vehicle- and naïve-MSC-treated mice. Changes in neurogenesis and Y-maze performance were negatively and significantly correlated with sICAM, CCL2, and CCL12 serum levels. We conclude that polarized PACAP-treated MSC present anti-inflammatory properties that can mitigate age-related changes in the systemic inflammatory milieu and, as a result, ameliorate age related cognitive decline.
In other stem cell news:
To ward off aging, stem cells must take out the trash
"In most cells, damaged or misfolded proteins get individually tagged for disposal. A mobile protein destroyer called the proteasome then finds the labeled proteins and breaks them down into their original amino acid components. But in the new study, the researchers found proteasome activity was especially low in HSCs. This left the team puzzled: if getting rid of damaged proteins is so important to stem cells, why is the proteasome less active?
Through a series of subsequent experiments, the team discovered that HSCs use a different system entirely. Here, damaged and misfolded proteins are collected and trafficked into clusters called aggresomes. Once corralled into a single location, they can be collectively destroyed by the lysosome (a cell organelle containing digestive enzymes) in a process called aggrephagy.
"What's very unusual here is this pathway was thought to only be triggered as an extreme stress response, but it's actually the normal physiological pathway that's used by stem cells," said Signer. "This emphasizes how critical it is for stem cells to prevent stress so they can preserve their health and longevity." "