title: Hepatocyte senescence in vivo following preconditioning for liver repopulation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Serra
authors.forename: Fabio
authors.initials: F
authors.lastname: Marongiu
authors.forename: Marcella
authors.initials: M
authors.lastname: Sini
authors.forename: Ezio
authors.initials: E
authors.lastname: Laconi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D017690:Cell Transplantation / Q000379:methods; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology; D008297:Male; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D019172:Transplantation Conditioning / Q000379:methods*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D015850:Interleukin-6; D011763:Pyrrolizidine Alkaloids; D001616:beta-Galactosidase; C003300:retrorsine