Abstract
BackgroundStem cell senescence has been proposed as one of the major drivers of aging, and MSC senescence contributes to aging-related diseases. Activation of mTORC1 pathway and heterochromatin organization have been characterized as two characteristics of senescent cells; however, whether mTORC1 pathway interacts with heterochromatin organization and contributes to MSC senescence remains unknown. In this study, we investigated the interaction between heterochromatin organization and mTORC1/p70S6K pathway in stress-induced MSC senescence.MethodsThe stress-induced senescence models were established in human umbilical cord-derived MSCs by doxorubicin (Dox) or H2O2. Cellular senescence was evaluated by β-Gal activity, upregulation of cell cycle suppressor genes, and expression of SASP. Activation of heterochromatin organization and mTORC1 pathway was determined by Western blot and immunofluorescent staining. A D-galactose (D-Gal)-induced aging model was established in rats to evaluate the crosstalk between heterochromatin and mTORC1 pathway in vivo.ResultsWe found that heterochromatin organization was provoked at the early stage of Dox- or H2O2-induced senescence. Disruption of heterochromatin organization led to robust DNA damage response and exacerbated cellular senescence. Suppression of mTORC1/p70S6K pathway by either rapamycin or p70S6K knockdown promoted heterochromatin organization and ameliorated Dox- or H2O2-induced DNA damage and senescence. In contrast, direct activation of mTORC1 by MHY1485 impaired heterochromatin organization and aggravated stress-induced senescence. Moreover, concomitant activation of mTORC1 pathway and heterochromatin organization was found in D-galactose-induced osteoporosis model in rats. Rapamycin alleviated cellular senescence and promoted heterochromatin organization in BMSCs derived from D-galactose-treated rats.ConclusionsAltogether, our study indicates the existence of a complex interplay between the mTORC1/p70S6K pathway and the heterochromatin organization during stress-induced MSC senescence, with important implications for the understanding of aging as well as for its prevention and treatment.
Highlights
Stem cell senescence has been proposed as one of the major drivers of aging, and Mesenchymal stromal cells (MSC) senescence contributes to aging-related diseases
Altogether, our study indicates the existence of a complex interplay between the mammalian target of rapamycin complex 1 (mTORC1)/Ribosomal protein S6 kinase (p70S6K) pathway and the heterochromatin organization during stress-induced MSC senescence, with important implications for the understanding of aging as well as for its prevention and treatment
Our real-time PCR results showed that the expression levels of the major members of senescence-associated secretory phenotype (SASP) were markedly increased along with the cellular senescence process induced by Dox or H2O2 (Fig. 1d)
Summary
Stem cell senescence has been proposed as one of the major drivers of aging, and MSC senescence contributes to aging-related diseases. In recent years, accumulating evidence shows that persistent activation of the growth-promoting mammalian target of rapamycin complex 1 (mTORC1) pathway plays a critical role in cellular senescence and organismal aging [5, 6]. Deficiency of mTORC1 substrate S6K1 increased lifespan in female but not in male mice [11] These findings suggest an evolutionary conserved role of mTORC1 in regulating aging and longevity. While the exact mechanism by which mTORC1 inhibition protects from cellular senescence and organismal aging remains unclear, the anti-aging effects have been associated with reduced accumulation of reactive oxygen species [14] and DNA damage [15], decreased secretion of SASP [16], switch of cellular energy metabolism [6], and reduced expression of tumor suppressors such as p16INK4A [17]
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