TY - JOUR
T1 - Functional crosstalk between mTORC1/p70S6K pathway and heterochromatin organization in stress-induced senescence of MSCs
AU - Liu, Hailong
AU - Huang, Biao
AU - Xue, Shaolong
AU - Kin Pong, U.
AU - Tsang, Lai Ling
AU - Zhang, Xiaohu
AU - Li, Gang
AU - Jiang, Xiaohua
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/7/13
Y1 - 2020/7/13
N2 - 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.
AB - 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.
KW - Aging
KW - Heterochromatin
KW - MSC senescence
KW - mTORC1/p70S6K
UR - http://www.scopus.com/inward/record.url?scp=85088016271&partnerID=8YFLogxK
U2 - 10.1186/s13287-020-01798-1
DO - 10.1186/s13287-020-01798-1
M3 - Article
C2 - 32660632
AN - SCOPUS:85088016271
VL - 11
JO - Stem Cell Research and Therapy
JF - Stem Cell Research and Therapy
IS - 1
M1 - 279
ER -