April 26, 2012

Rapamycin increases oxidative stress response gene expression in adult stem cells

Rapamycin increases oxidative stress response gene expression in adult stem cells

Balancing quiescence with proliferation is of paramount importance for adult stem cells in order to avoid hyperproliferation and cell depletion. In some models, stem cell exhaustion may be reversed with the drug rapamycin, which was shown can suppress cellular senescencein vitro and extend lifespan in animals. We hypothesized that rapamycin increases the expression of oxidative stress response genes in adult stem cells, and that these gene activities diminish with age. To test our hypothesis, we exposed mice to rapamycin and then examined the transcriptome of their spermatogonial stem cells (SSCs). Gene expression microarray analysis revealed that numerous oxidative stress response genes were upregulated upon rapamycin treatment, including superoxide dismutase 1, glutathione reductase, and delta-aminolevulinate dehydratase. When we examined the expression of these genes in 55-week-old wild type SSCs, their levels were significantly reduced compared to 3-week-old SSCs, suggesting that their downregulation is coincident with the aging process in adult stem cells. We conclude that rapamycin-induced stimulation of oxidative stress response genes may promote cellular longevity in SSCs, while a decline in gene expression in aged stem cells could reflect the SSCs' diminished potential to alleviate oxidative stress, a hallmark of aging.

Given that rapamycin has been shown to increase lifespan in aging mice, and that here it significantly enhanced the expression of Alad, Sod1, and Gsr in juvenile SSCs (spermatogonial stem cells), we next asked whether the levels of these three oxidative stress response transcripts were diminished in the SSCs isolated from older versus younger wild type mice. When SSCs from 55-week-old males were compared to SSCs from 3-week-old males, the relative gene expression values for Alad, Sod1, and Gsr were all decreased (1.46-, 1.72-, and 1.62-fold, respectively; p less than 0.05). Morphologically, the SSCs (spermatogonial stem cells) from the two ages of mice were indistinguishable, although fewer SSCs were obtained from the older testes than from the younger testes (data not shown). These data suggest that as SSCs age in vivo, the aging process correlates with a downregulation in the expression of genes that respond to oxidative stress.

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