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The study, published this week in Nature, identifies a previously unknown subset of blood stem cells that are shaped by past inflammatory events. These cells appear to accumulate over time and may influence how the immune system functions later in life.
Blood stem cells, found in the bone marrow, are responsible for producing all the body’s blood and immune cells. They must carefully balance two roles: generating new cells when needed – such as during infection – and preserving a stable pool of stem cells over decades.
While blood stem cells respond to short-term inflammation by stimulating production of more blood cells, repeated or chronic inflammation causes them to become dysfunctional and depleted. Inflammation has also been linked to stem cell ageing and to “clonal haematopoiesis” – an age-related condition where mutated blood stem cells expand over time, associated with a higher risk of leukaemia and other blood cancers. However, it has remained unclear precisely how human blood stem cells respond to inflammatory stress over time.
Researchers from the Vyas Group in the MRC Weatherall Institute of Molecular Medicine at the University of Oxford collaborated with the Dick and Xie labs at the University of Toronto and UHN’s Princess Margaret Cancer Centre to investigate how blood stem cells respond to and recover from inflammation. The team used experimental models alongside analysis of human bone marrow samples to show that blood stem cells do not respond uniformly. Instead, they identified two distinct groups.
One subset of stem cells returns to its original state after inflammation, while the other retains long-lasting changes in gene activity – effectively “remembering” the inflammatory stress. Researchers named the second group “inflammatory memory blood stem cells”. These two subsets of stem cells were observed both in mouse models, where transplanted human stem cells were exposed to repeated inflammatory stress, and in bone marrow samples from healthy individuals.
In healthy adults, these “inflammatory memory” cells became more common with age and were strongly linked to the presence of clonal haematopoiesis mutations that increase the risk of leukaemia. These mutations seem to have the greatest impact in inflammatory memory stem cells, where they counteract the effects of inflammatory stress and appear to keep them more active. This suggests that inflammatory memory may provide conditions in which mutated stem cells grow more readily.
“This study gives us a new way to think about how the body's past experiences of inflammation may shape future health. Blood stem cells are long-lived, and our findings suggest they can carry a molecular record of inflammatory stress, one that may help explain why people of similar ages can have very different risks of age-related disease,” said Professor Philip Awadalla, Professor of Molecular Genetics and co-Director of the Translational Epidemiology Unit at Oxford Population Health.
Researchers also identified links between inflammatory memory cells and conditions associated with chronic inflammation, including recovery from severe COVID-19 and sickle cell disease. Importantly, the study found that inflammatory memory stem cells “pass on” their inflammatory memory to the immune cells they produce.
The findings suggest that inflammatory history may leave a lasting imprint on the blood system, influencing immune function and disease risk over time. Dr Asger Jakobsen, co-first author of the study, said:
Our findings suggest that inflammatory memory blood stem cells may be an important link between inflammatory history, stem cell ageing, and the emergence of mutated stem cells that can progress to blood cancer. This may also partly explain why the presence of mutations in the blood system (known as clonal haematopoiesis) are associated with inflammation - i.e. it may be due to accumulation of inflammatory memory stem cells rather than the presence of the mutation alone. Given that blood stem cells give rise to all our immune cells, inflammatory memory stem cells may be important in additional disease settings, including inflammatory disorders and age-related diseases in multiple tissues where immune cells play a role.
Read the full article in Nature: Human hematopoietic stem cells remember inflammatory stress
In the MRC WIMM, this research was supported by the UKRI Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Oxford.