SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells

• Published in: Cell reports (Cambridge) Vol. 28; no. 13; pp. 3329 - 3337.e5
• Main Authors: Wiley, Christopher D., Liu, Su, Limbad, Chandani, Zawadzka, Anna M., Beck, Jennifer, Demaria, Marco, Artwood, Robert, Alimirah, Fatouma, Lopez-Dominguez, Jose-Alberto, Kuehnemann, Chisaka, Danielson, Steven R., Basisty, Natan, Kasler, Herbert G., Oron, Tal Ronnen, Desprez, Pierre-Yves, Mooney, Sean D., Gibson, Bradford W., Schilling, Birgit, Campisi, Judith, Kapahi, Pankaj
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.09.2019; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; aging; cellular senescence; Cellular Senescence - genetics; chemotherapy; clotting; coagulation; Hemostasis; homeostasis; Humans; proteomics; SASP; secretion; thrombosis; homeostasis; cellular senescence; thrombosis; secretion; clotting; proteomics; aging; coagulation; chemotherapy; SASP
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.08.049

Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence. We validated the expression of some of these SASP factors in cultured cells and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, selective removal of senescent cells using transgenic p16-3MR mice showed that clearing senescent cells attenuates the increased clotting caused by doxorubicin. Our study provides an in-depth, unbiased analysis of the SASP and unveils a function for cellular senescence in hemostasis. [Display omitted] •An unbiased SILAC screen identifies >300 proteins secreted by senescent human cells•Forty-four of these proteins have reported roles in hemostasis•Conditioned media from senescent cells promotes platelet activation•Eliminating senescent cells ameliorates pro-coagulation side effects of doxorubicin Wiley et al. identify new proteins secreted by senescent cells using unbiased proteomics, including factors involved in hemostasis. Secretions of senescent cells increase human platelet activation, while eliminating senescent cells prevents increases in platelet counts and activation in mice treated with chemotherapy. Senescent cells may thus underlie clotting predisposition.