These authors contributed equally to this work.
Hepatocyte senescence in vivo following preconditioning for liver repopulation†
Article first published online: 11 JUN 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 2, pages 760–768, August 2012
How to Cite
Serra, M. P., Marongiu, F., Sini, M. and Laconi, E. (2012), Hepatocyte senescence in vivo following preconditioning for liver repopulation. Hepatology, 56: 760–768. doi: 10.1002/hep.25698
Potential conflict of interest: Nothing to report.
- Issue published online: 25 JUL 2012
- Article first published online: 11 JUN 2012
- Accepted manuscript online: 5 MAR 2012 08:17AM EST
- Manuscript Accepted: 23 FEB 2012
- Manuscript Received: 5 JAN 2012
- AIRC (Italian Association for Cancer Research. Grant Number: IG 10604
In the retrorsine (RS)-based model of massive liver repopulation, preexposure to this naturally occurring alkaloid is sufficient to prime normal host parenchymal cells to be slowly replaced by transplanted normal hepatocytes. The basis for this striking effect is yet to be fully elucidated. In the present studies the possible involvement of cell senescence was investigated. Fischer 344 rats were treated according to the RS-based protocol for hepatocyte transplantation, i.e., two doses of RS, 2 weeks apart, and were killed at 4 or 8 weeks after treatment. Control groups were given saline. Expression of senescence-associated beta-galactosidase was greatly induced in hepatocytes exposed to RS. In addition, several other changes that have been related to cell senescence were observed: these included markers of persistent activation of a DNA damage response, an increased expression of mammalian target of rapamycin, and positive regulators of the cell cycle, together with the induction of p21 and p27 cyclin-dependent kinase inhibitors. Furthermore, RS treatment increased levels of interleukin-6 in the liver, consistent with the activation of a senescence-associated secretory phenotype. Conclusion: These findings indicate that RS induces hepatocyte senescence in vivo. We propose that cell senescence and the associated secretory phenotype can contribute to the selective growth of transplanted hepatocytes in this system. (HEPATOLOGY 2012)