Aged marrow macrophages expand platelet-biased hematopoietic stem cells via Interleukin1B.

ABSTRACT: The bone marrow microenvironment (BMME) 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?s) directs HSC platelet-bias. M?s from the marrow of aged mice and humans exhibited an activated phenotype, with increased expression of inflammatory signals. Aged marrow M?s also displayed decreased phagocytic function. Senescent neutrophils, typically cleared by marrow M?s, were markedly increased in aged mice, consistent with functional defects in M? phagocytosis and efferocytosis. In aged mice, Interleukin 1B (IL1B) was elevated in the bone marrow and caspase 1 activity, which can process pro-IL1B, was increased in marrow M?s and neutrophils. Mechanistically, IL1B 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?s induce the acquisition of platelet bias in aged HSCs. This work highlights the instructive role of M?s and IL1B in the age-associated lineage-skewing of HSCs, and reveals the therapeutic potential of their manipulation as antigeronic targets.

SUBMITTER: Frisch BJ 

PROVIDER: S-EPMC6542605 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature