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Background   Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow niches with tightly controlled reactive oxygen species (ROS) levels. ROS increase results into LT-HSC differentiation and stem cell exhaustion. Paraoxonase 2 (PON2) has been shown to be important for ROS control.Objectives   We investigate the effects of inactivation of the  PON2  gene on hematopoietic cell differentiation and activity.Methods and Results   In young mice with inactivated  Pon2  gene ( Pon2  −/− , <3 months), we observed an increase of LT-HSCs and a reduced frequency of progenitor cells. In competitive transplantations, young  Pon2 −/−   BM outcompeted WT BM at early time points. ROS levels were significantly increased in  Pon2 −/−   whole BM, but not in  Pon2 −/−   LT-HSCs. In more differentiated stages of hematopoiesis,  Pon2  deficiency led to a misbalanced erythropoiesis both in physiologic and stress conditions. In older mice (>9 months),  Pon2  depletion caused an increase in LT-HSCs as well as increased levels of granulocyte/macrophage progenitors (GMPs) and myeloid skewing, indicating a premature aging phenotype. No significant changes in ROS levels in old  Pon2 −/−   LT- and short-term (ST-) HSCs were observed, but a significant reduction of spontaneous apoptotic cell death was measured. RNA-seq analysis in  Pon2  −/−  LT-HSCs identified overrepresentation of genes involved in the C-X-C chemokine receptor type 4 (Cxcr4) signaling, suggesting compensatory mechanisms to overcome ROS-mediated accelerated aging in hematopoietic progenitor cells.Conclusions   In summary, our current data indicate that PON2 is involved in the regulation of HSC functions.

Deficiency of Antioxidative Paraoxonase 2 (Pon2) Leads to Increased Number of Phenotypic LT-HSCs and Disturbed Erythropoiesis