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Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression

Wijayasiri, Pramudi; Astbury, Stuart; Kaye, Philip; Oakley, Fiona; Alexander, Graeme J.; Kendall, Timothy J.; Aravinthan, Aloysious D.

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Authors

Pramudi Wijayasiri

Philip Kaye

Fiona Oakley

Graeme J. Alexander

Timothy J. Kendall



Abstract

Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this 'proof of concept' study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis.

Citation

Wijayasiri, P., Astbury, S., Kaye, P., Oakley, F., Alexander, G. J., Kendall, T. J., & Aravinthan, A. D. (2022). Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression. Cells, 11(14), Article 2221. https://doi.org/10.3390/cells11142221

Journal Article Type Article
Acceptance Date Jul 15, 2022
Online Publication Date Jul 17, 2022
Publication Date Jul 17, 2022
Deposit Date Jul 23, 2022
Publicly Available Date Mar 29, 2024
Journal Cells
Electronic ISSN 2073-4409
Publisher MDPI AG
Peer Reviewed Peer Reviewed
Volume 11
Issue 14
Article Number 2221
DOI https://doi.org/10.3390/cells11142221
Keywords hepatocyte senescence, liver fibrosis, stellate cell activation
Public URL https://nottingham-repository.worktribe.com/output/9093114
Publisher URL https://www.mdpi.com/2073-4409/11/14/2221

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