A groundbreaking study published in Nature reveals that human hematopoietic stem cells (HSCs) possess a remarkable capability to “remember” inflammatory stress experienced during severe infections. This memory, encoded in a unique transcriptional program termed the HSC inflammatory memory (HSC-iM), was uncovered through cutting-edge single-cell multi-omic profiling. The research sheds light on how past inflammatory insults shape the behavior and fate of stem cells, with far-reaching implications for aging, chronic diseases, and infection recovery.
In one of the most compelling findings, HSCs isolated from patients recovering from severe COVID-19 infection displayed a pronounced enrichment of the HSC-iM program compared with HSCs from patients admitted to intensive care units (ICU) for non-COVID reasons and healthy donors. This enrichment was evident at both the chromatin accessibility and gene expression levels, indicating a robust, long-lasting imprint left by the inflammatory milieu experienced during the critical illness phase. Intriguingly, a distinct set of 20 genes was identified as a post-COVID HSC transcriptional signature. These differentially expressed genes (DEGs) were uniquely upregulated in HSCs from post-COVID patients, confirming the specificity and persistence of this inflammatory memory.
The study’s authors leveraged gene set enrichment analysis (GSEA) to contextualize the HSC-iM program within thousands of known gene pathways and signatures. Remarkably, the HSC-iM program exhibited the highest statistical significance in enrichment when comparing ICU-COVID HSCs with other groups. This finding underscores the unique transcriptional changes that severe COVID-19 infection induces in hematopoietic stem cells and raises the possibility that this memory state influences immune recovery and resilience against subsequent infections or inflammatory insults.
Beyond infection recovery, the implications of HSC inflammatory memory extend deeply into the aging process. Chronic low-grade inflammation, or “inflammaging,” is a well-established hallmark of physiological aging that contributes to diminished tissue regeneration and escalated disease risk. By analyzing over 23,000 HSC transcriptomes from donors aged 19 to 87 years across multiple bone marrow cohorts, the research revealed a clear increase in HSC-iM program enrichment in the HSCs from older and middle-aged adults compared to young donors. These results suggest that the inflammatory memory program accumulates progressively with age, potentially priming aged HSCs to altered inflammatory responses and functional decline.
In parallel, the study demonstrated that the aged HSC transcriptomic changes converge on the HSC-iM signature, reinforcing that inflammation is a critical driver of age-associated stem cell remodeling. DEGs upregulated in aged HSC populations overlapped significantly with the HSC-iM genes, and the program’s chromatin accessibility was also enhanced in older individuals. Furthermore, a meta-signature of 37 aging-related genes, enriched for inflammatory regulators such as NR4A1 known to modulate inflammation resistance in clonal hematopoiesis, was identified. This meta-signature robustly distinguished HSC-iM-positive cells from their inflammatory-naive counterparts, highlighting molecular underpinnings linking inflammation, aging, and stem cell dysfunction.
Adding an important clinical dimension, the researchers investigated HSC-iM status in hematopoietic stem cells from pediatric patients with sickle cell disease (SCD), a condition characterized by chronic inflammation and premature aging phenotypes. Strikingly, the HSC-iM program was significantly enriched in SCD patients’ HSCs compared to healthy donors. This suggests that the inflammatory memory signature is not only a feature of physiological aging but also arises in disease states with persistent inflammatory stress. The variable expression of HSC-iM within SCD patient samples further reflects disease heterogeneity and may offer a window into how inflammation shapes stem cell dynamics in different clinical settings.
The robust link between severe infection, inflammation, and stem cell memory revealed by this study challenges previous assumptions that hematopoietic stem cells are transiently influenced by inflammatory cues. Instead, it posits that HSCs can undergo durable epigenetic and transcriptional remodeling, creating a poised state that could affect their function long after the inciting event has resolved. This concept invites new lines of inquiry into how inflammatory memory might contribute to long-term immune alterations and hematological disorders following critical illnesses.
Furthermore, the demonstration that aging-associated changes in HSCs are tightly coupled with HSC-iM suggests that therapeutic strategies aiming to modulate inflammatory pathways might delay or reverse deleterious aspects of stem cell aging. Such interventions could have profound impacts on healthspan, reducing susceptibility to infections, anemia, and malignancies that increase with age. The integration of multiple dataset comparisons in this study strengthens confidence in the reproducibility and biological relevance of these findings.
The study’s design utilized advanced single-cell multiome profiling, an integrative approach capturing both chromatin accessibility and gene expression within individual cells. This enabled the high-resolution identification of HSC subsets with inflammatory memory features, underscoring the power of these technologies to dissect complex cellular states in human samples. By comparing HSC profiles from diverse cohorts, including critically ill patients, aged donors, and individuals with chronic disease, the researchers painted a comprehensive picture of how inflammation imprints on hematopoietic stem cells.
In the context of the ongoing COVID-19 pandemic and broader infectious disease challenges, understanding how HSCs remember and respond to severe inflammation opens new vistas for managing post-infectious immune dysfunction. This insight could inform the development of biomarkers predicting patient recovery trajectories as well as potential stem cell-targeted therapies to enhance immune system resilience.
Overall, Zeng et al. provide compelling evidence that human hematopoietic stem cells do not merely endure inflammatory stress temporarily but rather encode a transcriptional and epigenetic memory that elevates their inflammatory responsiveness as part of a lifelong adaptation to infection, aging, and disease. This revelation transforms our understanding of HSC biology and sets the stage for future studies to unravel the molecular mechanisms driving this memory and its clinical consequences.
As we decode the language of stem cell inflammatory memory, the prospect of harnessing or modulating this phenomenon offers exciting therapeutic potential. Whether it’s ameliorating age-related hematopoietic decline, optimizing immune recovery post-infection, or improving outcomes in chronic inflammatory diseases like sickle cell anemia, the implications are vast. This research heralds a new era in stem cell biology and regenerative medicine, where past inflammatory encounters shape future cellular responses with lasting health implications.
By bridging immunology, hematology, and aging biology, the study delivers a paradigm shift illuminating how systemic events resonate within the very root of blood cell production. Continued exploration of HSC inflammatory memory promises to unlock novel strategies to enhance human healthspan and combat the long-term sequelae of severe infections and chronic inflammatory states worldwide.
Subject of Research: Human hematopoietic stem cells and their transcriptional memory of inflammatory stress in infection, aging, and disease.
Article Title: Human haematopoietic stem cells remember inflammatory stress.
Article References:
Zeng, A.G.X., Nagree, M.S., Jakobsen, N.A. et al. Human haematopoietic stem cells remember inflammatory stress. Nature (2026). https://doi.org/10.1038/s41586-026-10522-7
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-026-10522-7
Keywords: Hematopoietic stem cells, inflammatory memory, COVID-19, aging, inflammaging, sickle cell disease, single-cell multiome, transcriptional program, epigenetics, immune recovery
Tags: aging and chronic disease stem cell memorychromatin accessibility in stem cells inflammationCOVID-19 impact on hematopoietic stem cellsdifferentially expressed genes post-COVIDgene expression stem cell inflammatory responseHSC gene signature severe infection recoveryHSC inflammatory memory transcriptional programhuman hematopoietic stem cells inflammatory memoryinflammation-induced stempost-COVID hematopoietic stem cell changessingle-cell multi-omic profiling stem cellstranscriptional imprinting in stem cells
