Researchers Identify HSC-iM Stem Cell Subset Linked to 200-Gene Inflammatory Memory and Mortality Risk
Updated
Updated · Nature.com · May 27
Researchers Identify HSC-iM Stem Cell Subset Linked to 200-Gene Inflammatory Memory and Mortality Risk
3 articles · Updated · Nature.com · May 27
Single-cell analyses and xenograft inflammation-recovery models identified a distinct human blood stem-cell state, HSC-iM, that preserves transcriptional and epigenetic memory after prior inflammatory stress.
Repeated TNF or LPS exposure left HSC-iM cells more quiescent and with reduced haematopoietic output, while inflammatory programs were retained mainly in this subset rather than in other HSCs.
The HSC-iM program was enriched in stem cells from severe COVID-19 recovery, sickle cell disease, ageing and clonal haematopoiesis, tying the subset to real-world inflammatory and age-related conditions.
In clonal haematopoiesis, mutations such as DNMT3A and TET2 altered HSC-iM most strongly, easing its differentiation restraint and potentially helping mutant clones expand.
A 200-gene HSC-iM signature also appeared in downstream immune cells and was associated in population-cohort analyses with higher all-cause mortality risk, suggesting lasting health effects from inflammatory history.
Our blood stem cells record a lifelong history of inflammation. Does this invisible scar predetermine our risk of cancer and death?
If stem cells remember past inflammation, can this cellular 'memory' be erased to slow aging and prevent future diseases?
HSC-iM and Inflammatory Memory: Transforming Our Understanding of Blood Stem Cells, Aging, and Disease
Overview
A recent discovery revealed a unique subset of human hematopoietic stem cells, called HSC-iM, that can remember past inflammatory stress. This memory is encoded through specific transcriptional and epigenetic changes, which act as a lasting blueprint within the cells. These changes persist long after the initial inflammation, allowing HSC-iM to influence how blood stem cells respond to future stress. This breakthrough fundamentally changes our understanding of blood stem cell biology and opens new possibilities for studying how inflammation shapes disease risk, aging, and immune function.