Human Blood Stem Cells Retain 'Memory' of Inflammatory Stress, Influencing Lifelong Health

A groundbreaking study published in Nature reveals that human haematopoietic stem cells (HSCs), the precursors to all blood cells, possess a remarkable ability to 'remember' past inflammatory stress. This discovery sheds new light on how our bodies respond to inflammation over a lifetime and has significant implications for understanding ageing, disease progression, and overall health outcomes. Inflammation is a critical biological process, but chronic or repeated inflammatory events can contribute to a range of health issues, including ageing and malignancy. While HSCs are known for their resilience in sustaining blood production throughout life despite numerous infections, the precise mechanisms by which human HSCs adapt to inflammatory stress have largely remained a mystery until now. Researchers developed innovative xenograft inflammation–recovery models and employed single-cell multiomics to meticulously analyze xenografted human HSCs. The investigation identified two distinct HSC subsets, one of which was termed 'HSC inflammatory memory' (HSC-iM). This HSC-iM subset remarkably retained a molecular memory of previous inflammatory treatments, exhibiting distinct transcriptional and epigenetic profiles. Functionally, these 'remembering' cells displayed quiescence and a restrained haematopoietic output, suggesting a long-term adaptive response to inflammation that alters their normal function. Crucially, the study established the physiological relevance of HSC-iM. The molecular program characteristic of HSC-iM was found to be enriched in HSCs from both adult and paediatric samples across a spectrum of conditions, including recovery from COVID-19, sickle cell disease, ageing, and clonal haematopoiesis. This broad presence validates the xenograft models and underscores that HSC-iM is not merely an experimental artifact but a genuine biological phenomenon with widespread implications in human health. Further insights revealed that clonal haematopoiesis mutations within the HSC-iM subset could attenuate the detrimental effects of inflammatory stress by promoting HSC activation and differentiation. Moreover, the research demonstrated that the pro-inflammatory transcriptional program embedded within HSC-iM could be transmitted to their differentiated immune progeny, indicating a lasting impact on the immune system's responsiveness. This transmission was observed in both xenograft and physiological settings, highlighting its potential role in chronic inflammatory conditions. Perhaps the most significant clinical finding is the association between HSC-iM program enrichment in circulating blood cells and a heightened risk score for all-cause mortality in population cohort analyses. This compelling correlation underscores the profound clinical relevance of this newly identified HSC subset, offering a novel mechanism for characterizing heterogeneous health outcomes across an individual's lifetime and opening new avenues for therapeutic interventions targeting inflammatory memory in stem cells.