Blood Extracellular Vesicles From Healthy Individuals Regulate Haematopoietic Stem Cells as Humans Age

Haematopoietic stem cells (HSCs) maintain balanced blood cell production in a process called haematopoiesis. 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 haematopoiesis, 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. We have characterized blood EVs from humans and determined that they are remarkably consistent with respect to size, concentration and total protein content, across healthy subjects aged 20-85 yr. When analyzing EV protein composition from mass spectroscopy data, our machine-learning-based algorithms are able to distinguish EV proteins based on age, and suggest that different cell types dominantly produce EVs released into the blood, which change over time. Importantly, our data shows blood EVs from middle and older age groups (>40 yr) significantly stimulate haematopoietic stem cells (HSCs) in contrast to untreated and EVs sourced from young subjects. Our study establishes for the first time that although EV particle size, concentration and total protein content remain relatively consistent over an adult lifespan in humans, EV content evolves during aging and potentially influences HSC regulation.