title: Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells.
abstract: Stem cells of highly regenerative organs including blood are susceptible to endogenous DNA damage caused by both intrinsic and extrinsic stress. Response mechanisms to such stress equipped in hematopoietic stem cells (HSCs) are crucial in sustaining hematopoietic homeostasis but remain largely unknown. In this study, we demonstrate that serial transplantation of human HSCs into immunodeficient mice triggers replication stress that induces incremental elevation of intracellular reactive oxygen species (ROS) levels and the accumulation of persistent DNA damage within the human HSCs. This accumulation of DNA damage is also detected in HSCs of clinical HSC transplant patients and elderly individuals. A forced increase of intracellular levels of ROS by treatment with a glutathione synthetase inhibitor aggravates the extent of DNA damage, resulting in the functional impairment of HSCs in vivo. The oxidative DNA damage activates the expression of cell-cycle inhibitors in a HSC specific manner, leading to the premature senescence among HSCs, and ultimately to the loss of stem cell function. Importantly, treatment with an antioxidant can antagonize the oxidative DNA damage and eventual HSC dysfunction. The study reveals that ROS play a causative role for DNA damage and the regulation of ROS have a major influence on human HSC aging.
authors: Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors: Takashi
authors: T
authors: Yahata
authors: Tomomi
authors: T
authors: Takanashi
authors: Yukari
authors: Y
authors: Muguruma
authors: Abd Aziz
authors: AA
authors: Ibrahim
authors: Hideyuki
authors: H
authors: Matsuzawa
authors: Tomoko
authors: T
authors: Uno
authors: Yin
authors: Y
authors: Sheng
authors: Makoto
authors: M
authors: Onizuka
authors: Mamoru
authors: M
authors: Ito
authors: Shunichi
authors: S
authors: Kato
authors: Kiyoshi
authors: K
authors: Ando
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D017382:Reactive Oxygen Species