Functional crosstalk between mTORC1/p70S6K pathway and heterochromatin organization in stress-induced senescence of MSCs

BACKGROUND: Stem 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. METHODS: The stress-induced senescence models were established in human umbilical cord-derived MSCs by doxorubicin (Dox) or H(2)O(2). 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. RESULTS: We found that heterochromatin organization was provoked at the early stage of Dox- or H(2)O(2)-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 H(2)O(2)-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. CONCLUSIONS: Altogether, 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.