title: Impairment of Host Liver Repopulation by Transplanted Hepatocytes in Aged Rats and the Release by Short-Term Growth Hormone Treatment.
abstract: Hepatocyte transplantation is an alternative to whole liver transplantation. Yet, efficient liver repopulation by transplanted hepatocytes is low in livers of old animals. This restraint might be because of the poor proliferative capacity of aged donor hepatocytes or the regenerative impairment of the recipient livers. The age-dependent liver repopulation by transplanted wild-type hepatocytes was investigated in juvenile and senescent rats deficient in dipeptidyl-peptidase IV. Repopulation was quantified by flow cytometry and histochemical estimation of dipeptidyl-peptidase IV enzyme activity of donor cells in the negative host liver. As a potential pathway involved, expression of cell cycle proteins was assessed. Irrespective of the age of the donor hepatocytes, large cell clusters appeared in juvenile, but only small clusters in senescent host livers. Because juvenile and senescent donor hepatocytes were likewise functional, host-derived factor(s) impaired senescent host liver repopulation. Growth hormone levels were significantly higher in juvenile than in senescent rats, suggesting that growth hormone might promote host liver repopulation. Indeed, short-term treatment with growth hormone augmented senescent host liver repopulation involving the growth hormone-mediated release of the transcriptional blockade of genes associated with cell cycle progression. Short-term growth hormone substitution might improve liver repopulation by transplanted hepatocytes, thus augmenting the therapeutic benefit of clinical hepatocyte transplantation in older patients.
authors.affiliation: Division of Applied Molecular Hepatology, Clinics and Policlinics of Visceral, Transplantation, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany. Electronic address: peggy.stock@medizin.uni-leipzig.de.
authors.forename: Peggy
authors.initials: P
authors.lastname: Stock
authors.affiliation: Endocrine Research Unit, Department of Internal Medicine IV, Ludwig Maximilian University, Munich, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Bielohuby
authors.affiliation: Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Staege
authors.affiliation: Division of Applied Molecular Hepatology, Clinics and Policlinics of Visceral, Transplantation, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany.
authors.forename: Mei-Ju
authors.initials: MJ
authors.lastname: Hsu
authors.affiliation: Endocrine Research Unit, Department of Internal Medicine IV, Ludwig Maximilian University, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.affiliation: Division of Applied Molecular Hepatology, Clinics and Policlinics of Visceral, Transplantation, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Christ
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D016000:Cluster Analysis; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D020869:Gene Expression Profiling; D063990:Gene Ontology; D013006:Growth Hormone / Q000097:blood / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000637:transplantation*; D006801:Humans; D008099:Liver / Q000166:cytology*; D008297:Male; D011916:Rats, Inbred F344
chemical_list: D013006:Growth Hormone; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D018819:Dipeptidyl Peptidase 4