Reactive oxygen species and hematopoietic stem cell senescence - PubMed (original) (raw)

Reactive oxygen species and hematopoietic stem cell senescence

Lijian Shao et al. Int J Hematol. 2011 Jul.

Abstract

Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic homeostasis and regeneration after injury for the entire lifespan of an organism through self-renewal, proliferation, differentiation, and mobilization. Their functions can be affected by reactive oxygen species (ROS) that are produced endogenously through cellular metabolism or after exposure to exogenous stress. At physiological levels, ROS function as signal molecules which can regulate a variety of cellular functions, including HSC proliferation, differentiation, and mobilization. However, an abnormal increase in ROS production occurs under various pathological conditions, which can inhibit HSC self-renewal and induce HSC senescence, resulting in premature exhaustion of HSCs and hematopoietic dysfunction. This review aims to provide a summary of a number of recent findings regarding the cellular sources of ROS in HSCs and the mechanisms of action whereby ROS induce HSC senescence. In particular, we highlight the roles of the p38 mitogen-activated protein kinase (p38)-p16(Ink4a) (p16) pathway in mediating ROS-induced HSC senescence.

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Figures

Fig. 1

Fig. 1

A hypothetic model for reactive oxygen species (ROS) to mediate the induction of hematopoietic stem cell (HSC) senescence under various pathophysiological conditions. Increased levels of ROS are produced by mitochondria and/or NADPH oxidases (NOXs) in HSCs when HSCs are exposed to stress, a high concentration of oxygen or after deletion of ATM, FoxOs, Bmi1, TSC1, and HIF1α. ROS can induce HSC senescence by activating the ATM-Chk2-p53-p21 pathway via induction of DNA double strand breaks (DSBs) and/or stimulating the p38 pathway. Both pathways converge at p16 for the induction of HSC senescence. In addition, activation of p53 can also induce the expression of various pro-apoptotic proteins to cause HSC apoptosis. ROS may induce HSC senescence and apoptosis in a dose-dependent manner. Both of them can be prevented by treatment with an antioxidant, such as _N_-acetyl-L-cysteine (NAC)

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