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