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The enzyme paraoxonase-2 modulates hematopoiesis through redox signaling

ABSTRACT: Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow (BM) niches with low levels of oxygen and reactive oxygen species (ROS). ROS enhancement results in differentiation of LT-HSCs. Redox disturbances are involved in BM failure and leukemia. Paraoxonase-2 (PON2) has been shown to be important for ROS control. However, the role of PON2 in the hematopoietic system has not been addressed. Analysis of young mice with inactivated Pon2 gene (Pon2-/- mice; 3 months) revealed changes in quantity of hematopoietic stem and progenitor cells (HSPCs), which indicate changes in cell differentiation. Experiments with aged PON2-/- mice (>9 months) showed alterations of the HSPC compartment indicating changed self-renewal ability of HSCs and myeloid skewing. Reciprocal BM transplantation reveals cell intrinsic as well as extrinsic phenotypes. We observed markedly enhanced superoxide levels in BM as well as slightly enhanced total ROS level in short term (ST)-HSCs and multipotent progenitor cells (MPPs) of young mice. In aged mice, total ROS level was slightly increased in all 3 fractions of the Lin-, Sca1+, ckit+ (LSK) population. No changes in the amount of DNA double-strand breaks in LSK cells and decreased apoptosis rates in LT-HSCs of young as well as LT- and ST-HSCs of aged PON2-/- mice were seen, indicating a strong compensation mechanism. Changes of gene expression in PON2-/- LT-HSCs identified by RNA sequencing strengthened our conclusions. Additionally, competitive and serial bone marrow transplantation experiments exposed advantages of PON2-/- BMCs in multi-lineage reconstitution. Collectively, these analyses propose PON2 as crucial redox control enzyme in HSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE122553 | GEO | 2021/07/20

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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The enzyme paraoxonase-2 modulates hematopoiesis through redox signaling

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