Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration

Irvine, Katharine M., Skoien, Richard, Bokil, Nilesh J., Melino, Michelle, Thomas, Gethin P., Loo, Dorothy, Gabrielli, Brian, Hill, Michelle M., Sweet, Matthew J., Clouston, Andrew D. and Powell, Elizabeth E. (2014) Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration. World Journal of Gastroenterology, 20 47: 17851-17862. doi:10.3748/wjg.v20.i47.17851

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Author Irvine, Katharine M.
Skoien, Richard
Bokil, Nilesh J.
Melino, Michelle
Thomas, Gethin P.
Loo, Dorothy
Gabrielli, Brian
Hill, Michelle M.
Sweet, Matthew J.
Clouston, Andrew D.
Powell, Elizabeth E.
Title Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration
Journal name World Journal of Gastroenterology   Check publisher's open access policy
ISSN 2219-2840
Publication date 2014-12-21
Year available 2014
Sub-type Article (original research)
DOI 10.3748/wjg.v20.i47.17851
Open Access Status DOI
Volume 20
Issue 47
Start page 17851
End page 17862
Total pages 12
Place of publication Pleasanton, United States
Publisher Baishideng Publishing Group
Collection year 2015
Language eng
Formatted abstract
AIM: To develop a model of stress-induced senescence to study the hepatocyte senescence associated secretory phenotype (SASP).

METHODS: Hydrogen peroxide treatment was used to induce senescence in the human HepG2 hepatocyte cell line. Senescence was confirmed by cytochemical staining for a panel of markers including Ki67, p21, heterochromatin protein 1β, and senescence-associated-β-galactosidase activity. Senescent hepatocytes were characterised by gene expression arrays and quantitative polymerase chain reaction (qPCR), and conditioned media was used in proteomic analyses, a human chemokine protein array, and cell migration assays to characterise the composition and function of the hepatocyte SASP.

RESULTS: Senescent hepatocytes induced classical markers of senescence (p21, heterochromatin protein 1β, and senescence-associated-β-galactosidase activity); and downregulated the proliferation marker, Ki67. Hepatocyte senescence induced a 4.6-fold increase in total secreted protein (P = 0.06) without major alterations in the protein profile. Senescence-induced genes were identified by microarray (Benjamini Hochberg-corrected P < 0.05); and, consistent with the increase in secreted protein, gene ontology analysis revealed a significant enrichment of secreted proteins among inducible genes. The hepatocyte SASP included characteristic factors such as interleukin (IL)-8 and IL-6, as well as novel components such as SAA4, IL-32 and Fibrinogen, which were validated by qPCR and/or chemokine protein array. Senescent hepatocyte-conditioned medium elicited migration of inflammatory (granulocyte-macrophage colony stimulating factor, GM-CSF-derived), but not non-inflammatory (CSF-1-derived) human macrophages (P = 0.022), which could contribute to a pro-inflammatory microenvironment in vivo, or facilitate the clearance of senescent cells.

CONCLUSION: Our novel model of hepatocyte senescence provides insights into mechanisms by which senescent hepatocytes may promote chronic liver disease pathogenesis.
Keyword Cell aging
Liver diseases
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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