Blood stem cells carry a lasting memory of inflammation, study finds
A University of Toronto-led team of researchers has identified a new type of stem cell that can pass on the memory of inflammatory stress.
Published recently in Nature, the findings provide insight into how environmental exposures can shape our long-term health, particularly around aging.
“We had a very simple question: do human stem cells remember past infections?” asks Stephanie Xie, a scientist at the University Health Network and an assistant professor of medical biophysics at U of T’s Temerty Faculty of Medicine.
Infections and injury trigger inflammation as part of the body’s natural response against harmful microbes and repair damaged tissues. As a person ages, they also develop chronic low-grade inflammation throughout the body. This so-called “inflammaging” contributes to the onset of age-related diseases like metabolic conditions and cardiovascular disease.
In the new study — which Xie co-led alongside John Dick, a senior scientist at UHN and professor of molecular geneticsat Temerty Medicine, and University of Oxford professor Paresh Vyas — the researchers developed an inflammation recovery model using human stem cells derived from cord blood. By transplanting these stem cells into immunocompromised mice, the researchers could examine, for the first time, how human stem cells respond to different types of inflammatory stress.
To Xie’s surprise, the researchers identified two unique subpopulations of stem cells.
The first group of stem cells did not respond to either inflammatory stimulus. The second subset, which the researchers named inflammatory memory stem cells, underwent significant cellular changes after being exposed to an inflammation trigger. Specifically, these cells altered which genes were expressed — several pro-inflammatory pathways were turned on — and which regions of their DNA were accessible to the cell’s protein machinery.
Xie’s research uses the haematopoietic, or blood, system to study the influence of genetics and the environment on why some people age well while others don’t. She says blood stem cells are particularly well-suited to study this problem because researchers can trace their genetic lineage and track the cellular and functional differences among various subpopulations.
In their paper, the researchers showed that many of the features of inflammatory memory stem cells were passed down to its descendant cells, highlighting how an early inflammation event can have long-lasting impacts on blood and immune cell function.
To confirm the relevance of their findings in a real-world context, Xie and her collaborators looked for inflammatory memory blood stem cells in people who had recovered from illness, healthy older adults and younger individuals. They found the newly discovered stem cells were more abundant in people who were hospitalized with severe COVID-19, adults aged 60 and older, and children with sickle cell disease. The inflammatory memory stem cells were also enriched in individuals with clonal haematopoiesis, an aging-related phenomenon that is often a precursor to blood cancer and heart disease.
The researchers next turned to the Ontario Health Study, one of Canada’s largest long-term health studies, to look at the potential health consequences of blood stem cells transmitting their inflammatory memory to their progeny blood and immune cells. They found that in young people, the presence of an inherited inflammatory signature in their immune cells was associated with a higher mortality risk score.
“Now it’s about taking these findings to the population level to really see if we have signatures that can perhaps serve as biomarkers,” says Xie.
Building on her current collaborations, she is expanding her research into bigger population cohorts to determine if reducing inflammation — for example, using GLP-1 medicines — can decrease the occurrence of clonal hematopoiesis and prevent blood cancers.
She is also interested in understanding the other subset of blood stem cells that showed no response to inflammatory stimulation and whether their ability to resist inflammation can be harnessed as a therapeutic.
Xie says that these findings underscore how our environment and actions can impact our health and serve as a reminder that we can take steps to change our health.
“Not all of it is out of our control,” she says. “Small things, like walking to work, can matter. Decreasing inflammation could have huge benefits for our health.”
This research was funded by the Canadian Institutes of Health Research, Princess Margaret Cancer Foundation and Terry Fox Research Institute.