Abstract
The signaling of reactive oxygen species (ROS) is essential for the maintenance of normal cellular function. However, whether and how ROS regulate stem cells are unclear. Here, we demonstrate that, in transgenic mice expressing the human manganese superoxide dismutase (MnSOD) gene, a scavenger of ROS in mitochondria, the number and function of mouse hematopoietic stem/progenitor cells (HSPC) under physiological conditions are enhanced. Importantly, giving MnTnBuOE-2-PyP5+(MnP), a redox- active MnSOD mimetic, to mouse primary bone marrow cells or to C57B/L6 mice significantly enhances the number of HSPCs. Mechanistically, MnP reduces superoxide to hydrogen peroxide, which activates intracellular Nrf2 signaling leading to the induction of antioxidant enzymes, including MnSOD and catalase, and mitochondrial uncoupling protein 3. The results reveal a novel role of ROS signaling in regulating stem cell function, and suggest a possible beneficial effect of MnP in treating pathological bone marrow cell loss and in increasing stem cell population for bone marrow transplantation.
Highlights
Hematopoietic stem cells (HSCs) have the capacity for self-renewal and multilineage differentiation
Since manganese superoxide dismutase (MnSOD) has a critical role in controlling reactive oxygen species (ROS) generated in mitochondria, we examined the effect of MnSOD on hemapoietic stem and progenitor cells (HSPCs) in transgenic mice expressing the human MnSOD gene
We have verified that MnSOD is located in the matrix of mitochondria and that there is no significant change in other antioxidant enzymes or small molecular weight antioxidants that may impact the cellular redox state
Summary
Hematopoietic stem cells (HSCs) have the capacity for self-renewal and multilineage differentiation. Some of the experimental evidence in support of this concept includes: 1) Direct measurement of the incorporation of 13C from glucose into lactate indicates that long term hematopoietic stem cells (LT-HSCs) rely on anaerobic glycolysis, and have lower rates of oxygen consumption and lower ATP levels than other cells in bone marrow [11]; 2) Forced activation of OXPHOS leads to loss of stem cell properties and increased differentiation and apoptosis [12]; 3) Inhibition of complex III of the mitochondrial respiratory chain using antimycin A or myxothiazol promotes human ESC self-renewal and pluripotency [13]; 4) Genetic ablation of Abbreviations: HSC, Hematopoietic stem cell; HSPCs, Hematopoietic stem progenitor cells; HPCs, Hematopoietic progenitor cells; ROS, Reactive oxygen species; OXPHOS, Oxidative phosphorylation; SOD, Superoxide dismutase; MnP, MnTnBuOE-2-PyP5+; CFU, Colony-forming unit; CAFC, Cobblestone area-forming cell; BMT, Bone marrow transplantations; TF, Transcription factor; OCR, Oxygen consumption rate; ETC, Electron transport chain; BMNCs, Bone marrow nucleated cells; MFI, Mean fluorescence intensity; Nrf, Nuclear factor (erythroid-derived 2)-like 2; CAT, Catalase; UCP3, mitochondrial uncoupling protein 3; ETS, E twenty-six transcription factors; LSK, Lin-, Sca1+, c-kit+ cells; Lin+, Lineage positive cells; MyPro, Myeloid Progenitor
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