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Distinct roles for NFκB in hematopoietic stem cells and the bone marrow milieu in promoting hematopoietic aging

ABSTRACT: Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, HSC accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes aging phenotypes. NFκB both responds to and directs inflammation, and we present an experimental model of elevated NFκB activity (“IκB–”) to dissect its role in hematopoietic aging phenotypes. We find that while elevated NFκB activity is not sufficient for HSC accumulation, HSC-autonomous NFκB activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the IκB– proinflammatory bone marrow milieu as observed functionally, epigenomically, and transcriptomically. A scRNA-seq HSPC labeling framework enables comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NFκB activity and quiescence, but not myeloid bias. These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable.

ORGANISM(S): Mus musculus

PROVIDER: GSE264569 | GEO | 2025/08/25

REPOSITORIES: GEO

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Distinct roles for NF-κB in hematopoietic stem cells and the bone marrow milieu in promoting hematopoietic aging

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