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Cited by 160Hematopoietic Stem Cell TransplantationPhagocytosis and Immune RegulationMesenchymal stem cell research

Aged marrow macrophages expand platelet-biased hematopoietic stem cells via interleukin-1B

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Frisch, Benjamin J., Hoffman, Corey M., Latchney, Sarah E., LaMere, Mark W., Myers, Jason, Ashton, John, Li, Allison J., Saunders, Jerry +13 more·2019·JCI Insight
DOI 10.1172/jci.insight.124213PMC PMC6542605
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Abstract

The bone marrow microenvironment contributes to the regulation of hematopoietic stem cell (HSC) function, though its role in age-associated lineage skewing is poorly understood. Here we show that dysfunction of aged marrow macrophages (Mφs) directs HSC platelet bias. Mφs from the marrow of aged mice and humans exhibited an activated phenotype, with increased expression of inflammatory signals. Aged marrow Mφs also displayed decreased phagocytic function. Senescent neutrophils, typically cleared by marrow Mφs, were markedly increased in aged mice, consistent with functional defects in Mφ phagocytosis and efferocytosis. In aged mice, interleukin-1B (IL-1B) was elevated in the bone marrow, and caspase-1 activity, which can process pro–IL-1B, was increased in marrow Mφs and neutrophils. Mechanistically, IL-1B signaling was necessary and sufficient to induce a platelet bias in HSCs. In young mice, depletion of phagocytic cell populations or loss of the efferocytic receptor Axl expanded platelet-biased HSCs. Our data support a model wherein increased inflammatory signals and decreased phagocytic function of aged marrow Mφs induce the acquisition of platelet bias in aged HSCs. This work highlights the instructive role of Mφs and IL-1B in the age-associated lineage skewing of HSCs, and reveals the therapeutic potential of their manipulation as antigeronic targets.

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Authors
Frisch, B. J., Hoffman, C. M., Latchney, S. E., LaMere, M. W., Myers, J., Ashton, J., Li, A. J., Saunders, J., Palis, J., Perkins, A. S., McCabe, A., Smith, J. N. P., McGrath, K. E., Rivera-Escalera, F., McDavid, A., Liesveld, J. L., Korshunov, V. A., Elliott, M. R., MacNamara, K. C., Becker, M. W., & Calvi, L. M.
Affiliations
  • Department of Medicine,
  • University of Rochester Medicine (US)
  • James P. Wilmot Cancer Institute, and
  • Albany Medical College (US)
  • Center for Pediatric Biomedical Research and
  • Department of Microbiology and Immunology,
  • Department of Biostatistics and Computational Biology, and
Corresponding author
  • MacNamara, Katherine C.
  • Calvi, Laura M.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2019-05-16
Volume
4
Issue
10
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.124213
PMC
PMC6542605
OpenAlex
W2938719760
Cited by
160
References
15
Citations by year
2026: 17 · 2025: 31 · 2024: 22 · 2023: 21 · 2022: 17 · 2021: 32 · 2020: 15 · 2019: 5
FWCI
12.19
Type
journal article
Language
en
Open access
Locations
  • JCI Insight (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (HL131184)
  • National Cancer Institute (CA166280)
  • National Institute of Allergy and Infectious Diseases (AI107276)
  • National Institute of General Medical Sciences (GM10699, GM105949)
  • National Institute on Aging (AG046293)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK098251)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
hematopoietic stem cells, IL-1β, bone marrow microenvironment, phagocytosis, efferocytosis, AXL receptor, caspase-1, inflammation, aging
MeSH terms
Axl Receptor Tyrosine Kinase, Aging, Animals, Blood Platelets, Bone Marrow, Hematopoietic Stem Cells, Humans, Macrophages, Male, Mice, Inbred C57BL, Neutrophils, Phagocytosis, Phenotype, Proto-Oncogene Proteins, Mice, Knockout, Caspase 1, Receptor Protein-Tyrosine Kinases, Mice, Interleukin-1beta

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