Developmental differences in the immortalization of lung fibroblasts by telomerase

Abstract

SummaryThe role of ambient (21%) and physiological oxygen (2-5%) in the immortalization of fetal vs. adult human lung fibroblasts was examined. Growth in low oxygen and antioxidants extended the lifespan of both fetal and adult strains. As the ectopic expression of telomerase could immortalize adult lung fibroblasts cultured in ambient oxygen, the lifespan-shortening effects of 21% oxygen must have been largely limited to telomeres. By contrast, fetal lung fibroblasts could not be immortalized in ambient oxygen in spite of telomere elongation by telomerase, suggesting more widespread oxidative damage. The longterm culture requirements for the immortalization of WI-38 fetal lung fibroblasts included supplementation with N-( tert ) butyl hydroxylamine, dexamethasone, zinc and vitamin B12, in addition to growth in physiological oxygen. The mechanisms regulating telomere shortening remain controversial. The present results suggest that both endreplication and oxidative damage events contribute to telomere shortening in lung fibroblasts in vitro . These observations emphasize the need for better analytical techniques to distinguish whether the correlation of short telomeres with disease and mortality in humans reflects the consequences of increased proliferation, telomere shortening as a result of oxidative damage or some combination of these processes.

The DNA Damage Signaling Pathway Connects Oncogenic Stress to Cellular Senescence

“…34,35 In fact, telomerase can not immortalize all isolates of human diploid fibroblasts when cells are grown in 20% oxygen. 36 These data indicate that replicative senescence is not only driven by the shortening of telomeres, but also by DNA damage induced by ROS. In fact, ROS can directly damage telomeres accelerating their erosion.…”

Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm

“…As oxidative stress heightens DNA damage and telomere loss [43,44], it may be a key determinant in aging-related diseases [45]. Thus, sperm with longer telomeres might arise from a subset of germ-line stem cells that either sustained less aging-related oxidative stress-perhaps because of increased resistance to its action-or underwent fewer replications prior to meiosis.…”

Paternal age and reproduction

“…The implications on the health of the offspring are unknown but a greater TL might represent a selection advantage. The increase of TL might be due to a selection during the numerous replications of germ-line stem cells, where only a subset of sperm with high TL resists the selection pressure of aging (Kimura et al, 2008), possibly mediated by oxidative stress (Forsyth et al, 2003).…”