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Human CD11b+ macrophages - Aging of hematopoietic stem cells is driven by regional specialization of marrow macrophages

ABSTRACT: The human aged hematopoietic system is prone to dysfunction and clonal selection. Aged hematopoietic stem cells (HSCs) have well-defined characteristics, but the contribution of the bone marrow microenvironment (BMME) to HSC ageing is unclear. We identify age-dependent changes in bone-associated (BA) and marrow-associated (MA) cell populations in murine and human marrow, where only aged MA cells induce aged HSC characteristics. MA aged macrophages (Mφs) could impart aged characteristics to both HSC and BMME populations, and demonstrated decreased ability to engulf senescent neutrophils. Moreover, removal of Mφs from young mice rapidly induced aged HSC characteristics. Interleukin-1β (IL-1β), a cytokine that is restrained when Mφs engulf apoptotic cells, was a key mediator of microenvironmental HSC aging. These data define a previously unknown role for aged MA Mφs to orchestrate BMME and HSC changes. Mφs and IL-1β may therefore represent novel targets for preventing or reversing hematopoietic defects due to advanced age.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100905 | GEO | 2019/06/10

REPOSITORIES: GEO

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Project description:Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and increased risk for myelodysplasia and leukemia. Deficient DNA repair contributes to the decline in HSC self-renewal capacity during aging and it remains unclear whether extrinsic signals can rejuvenate aged HSCs. Here, we demonstrate that augmentation of non-homologous end-joining (NHEJ) DNA repair in aged HSCs via treatment with epidermal growth factor (EGF) rejuvenates HSC function. Seven day culture of BM CD34-ckit+sca-1+lin- (34-KSL) HSCs from aged C57BL/6 mice with EGF suppressed myeloid skewing and increased production of multipotent CFU-granulocyte, erythroid, monocyte and megakaryocyte (CFU-GEMM) colonies. Aged, EGF-treated HSCs displayed increased donor multilineage engraftment in primary competitively transplanted mice and in secondary mice compared to mice transplanted with aged, control HSCs. Donor cell engraftment within the bone marrow (BM) KSL and SLAM+KSL HSC population was > 2-fold increased in mice transplanted with aged, EGF-treated HSCs. Systemic administration of EGF to aged mice for 6 weeks also increased long term – HSC self-renewal capacity as measured by increased donor bone marrow (BM) competitive repopulation in primary and secondary transplanted mice. Conversely, deletion of EGFR in Scl/Tal1+ hematopoietic cells was associated with increased myeloid skewing and depletion of LT-HSCs in middle aged mice. Mechanistically, EGF treatment decreased DNA damage in aged HSCs through activation of DNA PK-cs, Artemis and NHEJ repair. Inhibition of DNA PK-cs blocked EGF-mediated restoration of multipotent differentiation and suppression of myeloid skewing in aged HSCs, suggesting that the restoration of hematopoietic potential in aged HSCs is dependent on EGF-mediated activation of DNA PK-cs. EGF treatment also converted the transcriptome of aged HSCs from enrichment for genes involved in cell death and survival to genes involved in HSC generation and identity. These data suggest that extrinsic activation of EGFR signaling can restore key functional capacities in aged HSCs.

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Human CD11b+ macrophages - Aging of hematopoietic stem cells is driven by regional specialization of marrow macrophages

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