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

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 gene on hematopoietic cell differentiation and activity.

Methods And Results: In young mice with inactivated gene ( , <3 months), we observed an increase of LT-HSCs and a reduced frequency of progenitor cells. In competitive transplantations, young BM outcompeted WT BM at early time points. ROS levels were significantly increased in whole BM, but not in LT-HSCs. In more differentiated stages of hematopoiesis, deficiency led to a misbalanced erythropoiesis both in physiologic and stress conditions. In older mice (>9 months), 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 LT- and short-term (ST-) HSCs were observed, but a significant reduction of spontaneous apoptotic cell death was measured. RNA-seq analysis in 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.