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

Hailong Liu, Biao Huang, Shaolong Xue, U. Kin Pong, Lai Ling Tsang, Xiaohu Zhang, Gang Li, Xiaohua Jiang

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


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 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. Results: We 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. 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.

Original languageEnglish
Article number279
JournalStem Cell Research and Therapy
Issue number1
Publication statusPublished - 13 Jul 2020
Externally publishedYes


  • Aging
  • Heterochromatin
  • MSC senescence
  • mTORC1/p70S6K


Dive into the research topics of 'Functional crosstalk between mTORC1/p70S6K pathway and heterochromatin organization in stress-induced senescence of MSCs'. Together they form a unique fingerprint.

Cite this