title: Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin mitigates total body irradiation-induced long-term bone marrow suppression.
abstract: Our recent studies showed that total body irradiation (TBI) induces long-term bone marrow (BM) suppression in part by induction of hematopoietic stem cell (HSC) senescence through reactive oxygen species (ROS). In this study, we examined if Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin (MnTE), a superoxide dismutase mimetic and potent antioxidant, can mitigate TBI-induced long-term BM injury in a mouse model. Our results showed that post-TBI treatment with MnTE significantly inhibited the increases in ROS production and DNA damage in HSCs and the reduction in HSC frequency and clonogenic function induced by TBI. In fact, the clonogenic function of HSCs from irradiated mice after MnTE treatment was comparable to that of HSCs from normal controls on a per-HSC basis, suggesting that MnTE treatment inhibited the induction of HSC senescence by TBI. This suggestion is supported by the finding that MnTE treatment also reduced the expression of p16(Ink4a) (p16) mRNA in HSCs induced by TBI and improved the long-term and multilineage engraftment of irradiated HSCs after transplantation. Therefore, the results from this study demonstrate that MnTE has the potential to be used as a therapeutic agent to mitigate TBI-induced long-term BM suppression by inhibiting ionizing radiation-induced HSC senescence through the ROS-p16 pathway.
authors.affiliation: Institute of Radiation Medicine, Department of Biochemistry and Molecular Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Pazhanisamy
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Aimin
authors.initials: A
authors.lastname: Meng
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014916:Whole-Body Irradiation / Q000009:adverse effects*
chemical_list: D000975:Antioxidants; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin