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

Jennifer J Chia; Apeksha Singh; Yu-Sheng Lin; Noa Popko; David Mastro; Yi Liu; Tiffany Tran; Jennifer K King; Dinesh S Rao; Alexander Hoffmann

doi:10.1016/j.celrep.2025.116193

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

Cell Rep. 2025 Sep 23;44(9):116193. doi: 10.1016/j.celrep.2025.116193. Epub 2025 Aug 26.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; UCLA/Caltech Medical Scientist Training Program, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: ahoffmann@ucla.edu.

Abstract

Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, hematopoietic stem cell (HSC) accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes aging phenotypes. Nuclear factor κB (NF-κB) both responds to and directs inflammation, and we present an experimental model of elevated NF-κB activity ("inhibitor of κB deficient" [IκB^-]) to dissect its role in hematopoietic aging phenotypes. We find that while elevated NF-κB activity is not sufficient for HSC accumulation, HSC-autonomous NF-κB 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 single-cell RNA sequencing (scRNA-seq) HSPC labeling framework enables comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NF-κB 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.

Keywords: C/EBP; CP: Immunology; CP: Stem cell research; NF-κB; bone marrow cytokine milieu; bone marrow niche; hematopoietic aging; hematopoietic stem cell impairment; inflammaging; microenvironment; myeloid bias; stem cell aging.

MeSH terms

Aging*
Animals
Bone Marrow* / metabolism
Cellular Senescence*
Hematopoiesis*
Hematopoietic Stem Cells* / cytology
Hematopoietic Stem Cells* / metabolism
Humans
Inflammation / pathology
Mice
Mice, Inbred C57BL
NF-kappa B* / metabolism

Substances

NF-kappa B

Abstract

MeSH terms

Substances

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