Stem Cell Senescence: A Double-Edged Sword?

Extract

Local tumor control following irradiation, as evidenced by clonogenic survival, is achieved through the elimination of tumor stem cells. Logically, this beneficial effect could be deleterious when normal tissue stem cells are depleted. Few studies, however, document the importance of radiation-induced premature senescence in nonhematopoietic progenitor cells. The Citrin et al. article in this issue of the Journal ( 1 ) is among the first to reveal the biological significance of this process in epithelial precursor cells. Using molecular array and histochemical techniques, Citrin et al. found that alveolar epithelial type II (AECII) cells from irradiated C57BL/6NCr mice underwent dose-dependent senescence. Apoptosis was not dependent on dose or correlated with toxicity. The senescence increase was seen even when the number of AECII cells recovered. They propose that oxidative stress induces senescence and that depopulation of AECII progenitor cells leads to pulmonary inflammation and fibrosis.

Pathologists, as summarized by Fajardo et al., describe radiation injury as accelerated aging with persistent fibrosing inflammation and depopulation of epithelial cells ( 2 ). Chronic oxidative stress, such as proliferation and premature maturation of fibroblasts, is commonly assumed to be the stimulus for inflammation and a cause of this injury. Radiation-induced cellular damage has been demonized as the primary mechanism causing pulmonary injury, including endothelial cell apoptosis and fibroblast proliferation. Ultimately, the accumulation of mature fibroblasts produces excess collagen and causes downstream tissue damage and inflammation. Pathological studies regarding activated transforming growth factor beta (TGF-β), interleukin-1 alpha (IL-1α), and interleukin 6 (IL-6) support the notion of an inflammatory damage mechanism ( 3 , 4 ). In the present investigation, gene expression studies were performed with whole tissue extracts; therefore, they do not distinguish the mature pneumocytes from AECI cells, endothelial cells, fibroblasts, or AECII cells. However, the histological studies show that the fates of fibrosis and AECII cells are reciprocal, and the co-culture studies show that irradiation of AECII cells results in a lasting fibrogenic phenotype. These studies contribute to the discussion regarding the interaction between oxidative stress, inflammation, cytokine cascades, and now senescence.