Journal
JCI INSIGHT
Volume 4, Issue 10, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.124213
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Funding
- National Heart, Lung, and Blood Institute [F31 HL131184]
- National Institute of General Medical Sciences [K12 GM106997, R01 GM105949]
- National Institute of Allergy and Infectious Diseases [U01 AI107276, R01 AI114554]
- Department of Defense [W81XWH1810485]
- National Cancer Institute [R01 CA166280, F32 CA180615]
- National Institute on Aging [R01 AG046293]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK098251]
- Wilmot Cancer Institute
- U.S. Department of Defense (DOD) [W81XWH1810485] Funding Source: U.S. Department of Defense (DOD)
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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 (M phi s) directs HSC platelet bias. M phi s from the marrow of aged mice and humans exhibited an activated phenotype, with increased expression of inflammatory signals. Aged marrow M phi s also displayed decreased phagocytic function. Senescent neutrophils, typically cleared by marrow M phi s, were markedly increased in aged mice, consistent with functional defects in M phi phagocytosis and efferocytos is. 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 M phi s 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 M phi s induce the acquisition of platelet bias in aged HSCs. This work highlights the instructive role of M phi s 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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