Extracellular Vesicle Signals in Older Individuals Alter Hematopoietic Stem Cell Activity

Stem cell activity declines with age, due in part to damage to these cells and their niches, but perhaps to a greater degree due to changes in the signaling environment resulting from rising levels of molecular damage and consequent dysfunction throughout the body. Not all of these signaling changes are obviously harmful; some are attempts to compensate. Some of those attempts produce benefits, slowing the overall pace of decline, but also unwanted side-effects. Researchers here note that the contents of extracellular vesicles released by cells change with age, and that hematopoietic stem cells react to vesicles from older individuals with signs of increased activity. This may compensate in part for a trajectory of declining integrity and activity, but it may also contribute to the risk of cancers and other immune dysfunction arising from the clonal expansion of mutations in hematopoietic cell populations.

Hematopoietic stem cells (HSCs) maintain balanced blood cell production in a process called hematopoiesis. As humans age, their HSCs acquire mutations that allow some HSCs to disproportionately contribute to normal blood production. This process, known as age-related clonal hematopoiesis, predisposes certain individuals to cancer, cardiovascular, and pulmonary pathologies. There is a growing body of evidence suggesting that factors outside cells, such as extracellular vesicles (EVs), contribute to the disruption of stem cell homeostasis during aging.

The present study demonstrates that healthy individuals maintain circulating EVs consistent in terms of size, particle concentration, and total protein per particle between 20-85 years of age. In contrast, blood EV protein profile composition changes over time in humans, and our in silico analyses, suggests that certain organs or cell types may be responsible for this change, by altering EV production and releasing EVs into the bloodstream. Most strikingly, the blood circulating EVs produced from middle and older-aged individuals stimulate HSC colony-forming ability in contrast to younger individuals and untreated controls.

This work highlights that blood EVs impart important extracellular signals to HSCs as humans age. We posit that EVs may provide a compensatory stimulus that counter-balances a decrease in HSC functionality in individuals approaching middle-age. Current work is investigating how these activation signals, provided by the EVs, may impact the trajectory of expansion of mutations via clonal hematopoiesis, which may have profound implications in the development of hematological-based malignancies later in life. We demonstrate, for the first time a fundamental age-specific difference in blood EVs that specifically affects HSCs in individuals after 40 years of age, prior to the detection of classically defined clonal hematopoiesis.

Link: https://doi.org/10.1111/acel.13245


It would be good if a treatment along these lines could fix the decline in the supply of immature T and B cells with age.

It would also be interesting to see if there are any changes in extra cellular vesicles in the serum and their effect on HSC after some damage has been removed, say for exampe after a senolytic treatment.

Posted by: jimofoz at November 18th, 2020 10:42 AM

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