Ho Seok Lee

Inflammation activates blood cells, contributing to ageing and malignancy ^1–3 . Haematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long haematopoiesis ^1–9 , but how human HSCs respond and adapt to inflammatory stress is largely unknown. Here, to empirically understand this adaptation, we developed xenograft inflammation–recovery models and performed single-cell multiomics on xenografted human HSCs. Two transcriptionally and epigenetically distinct HSC subsets were identified with one, termed HSC inflammatory memory (HSC-iM), retaining a molecular memory of previous inflammatory treatments. The HSC-iM subset exhibited quiescence and restrained haematopoietic output. Molecularly, the HSC-iM program was enriched in HSCs from adult and paediatric samples across conditions ranging from COVID-19 recovery, sickle cell disease, ageing and clonal haematopoiesis, establishing both the validity of our xenograft models and the physiological relevance of HSC-iM. Clonal haematopoiesis mutations in HSC-iM attenuated the effects of inflammatory stress by promoting HSC activation and differentiation. Moreover, transmission of the pro-inflammatory HSC-iM transcriptional program to differentiated immune progeny was demonstrated in xenograft and physiological settings. Finally, HSC-iM program enrichment in circulating blood cells was associated with a heightened risk score for all-cause mortality in population cohort analyses, underscoring the clinical relevance of this newly identified HSC subset in characterizing heterogeneous health outcomes across a lifetime.

Cancer survivors experience long-term skeletal and hematopoietic complications that limit quality of life following chemotherapy (CTX), yet the mechanisms underlying these defects remain incompletely understood. Using a murine model of doxorubicin (DOX)-based leukemia induction therapy, we show that CTX induces inflammatory remodeling of the bone marrow (BM) niche. DOX treatment resulted in loss of arteriolar vasculature, blockade of mesenchymal stromal cell (MSC) differentiation, trabecular bone loss, and reduced niche capacity to maintain hematopoietic stem cells (HSCs). These defects were accompanied by aberrant immune activation within the BM, marked by increased interferon-γ (IFNγ) production by CD8⁺ T cells. Inhibition of IFNγ signaling partially restored arteriolar vessels and adipogenic differentiation. Moreover, combined IFNγ blockade and deferoxamine mesylate (DFM), which promotes vascular recovery, attenuated chemotherapy-associated skeletal damage. Consistent with these findings, paired BM samples collected at diagnosis and post-CTX from leukemia patients exhibited altered MSC lineage priming, upregulation of inflammatory pathways, and expansion of BM CD8⁺ memory T cells after treatment. Together, these findings implicate IFNγ-driven chronic inflammatory remodeling as a central mechanism of CTX-associated BM niche dysfunction and pinpoints inflammatory signaling as a potential target to preserve BM function and long-term tissue integrity.