FIG. 4.

A schematic diagram demonstrates the differential effect and graded response of HSCs to various redox-active compounds and ROS inducers. Normal hematopoiesis is characterized by primitive LT-HSCs that have the ability to self-renew and differentiate into any other cell type. As differentiation occurs, progenitor cell types lose their ability to self-renew. This process is accelerated in the presence of potent ROS induces, such as conventional chemotherapeutic agents and ionizing radiation. Response to these stimuli results in DNA damage response and activation of signaling that results in the upregulation of cellular senescence and apoptosis. New evidence now suggests that mild ROS inducers have an opposite effect wherein generation of a mild ROS milieu results in the activation of antioxidant defense pathways leading to an improvement in HSC function. The result is a graded response to different levels of ROS stimulant that leads to variations of HSC function and either exhaustion or strengthening of the hematopoietic niche. Atm, ataxia-telangiectsia mutated; BSO, buthionin sulfoximine; DOX, doxorubicin; MnP, Mn porphyrin; Nq01, NAD(P)H dehydrogenase quinone 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars