Loss of peroxisome function promotes oxidative stress induced hematopoiesis

Abstract The role of peroxisomes in hematopoiesis remains poorly understood. The PEX1-Gly844Asp knock-in mouse lacks peroxisome formation and is peroxisome deficient. We observed that peroxisome deficient animals had up to 50% greater numbers of peripheral lymphocytes, neutrophils, and platelets which contained 2-fold greater reactive oxygen species (ROS, p = 0.0002). The marrow contained 2-fold greater numbers of cells and CFU (p = 0.0009 and < 0.0001, respectively). We found expansion (up to 3-fold) in the hematopoietic stem and progenitor cell (HSPC) compartment compared to that of WT animals demonstrated by: in vivo enumeration of LSK (p < 0.0001). Importantly through competitive bone marrow transplant experiments (primary and secondary) we show that peroxisome deficient cells outcompete wild type. We further demonstrate that peroxisome deficient HSPC harbor very high levels of intrinsic reactive oxygen species (ROS) which are attenuated after repopulation. Isolation of mesenchymal stem cells (MSC) isolated from peroxisome deficient mice also showed elevated levels of ROS. Finally, we found elevated levels of stem cell factor (SCF) in the plasma of peroxisome deficient mice and peroxisome deficient MSC expressed 2-fold more SCF compared to WT. Chemical induction of ROS also increased SCF expression by MSC. LSK expanded >10-fold greater in the absence on SCF on peroxisome deficient MSC than on WT MSC. In conclusion, the increase in HSPC numbers is, in part, driven by response to ROS in the microenvironment leading to increased SCF. These data add new insight into the role of peroxisomes in the bone marrow niche.