title: A novel redox regulator, MnTnBuOE-2-PyP5+, enhances normal hematopoietic stem/progenitor cell function.
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.
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Carroll
authors.affiliation: Department of Neurosurgery, University of Texas, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: You
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chaiswing
authors.affiliation: Genetic Center, Women and Children's Healthcare, Qingdao, China.
authors.forename: R
authors.initials: R
authors.lastname: Wen
authors.affiliation: Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: I
authors.initials: I
authors.lastname: Batinic-Haberle
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Kentucky, Lexington, KY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bondada
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA. Electronic address: dstcl00@uky.edu.
authors.forename: D K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D008665:Metalloporphyrins; C575143:Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase
keywords: Mitochondrial; MnSOD; Nrf2; ROS; Stem