title: Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation.
abstract: Engraftment of donor hepatocytes is a critical step that determines the success of hepatocyte transplantation. Rapid and efficient integration of donor cells would enable prompt liver repopulation of these cells in response to selective proliferative stimuli offered by a preparative regimen. We have earlier demonstrated that hepatic irradiation (HIR) in combination with a variety of hepatotrophic growth signals, such as partial hepatectomy and hepatocyte growth factor, can be used as a preparative regimen for liver repopulation of transplanted hepatocytes. In this study, we investigated the effects of HIR on engraftment of transplanted dipeptidyl peptidase IV (DPPIV)-positive hepatocytes in congeneic DPPIV-deficient rats. HIR-induced apoptosis of hepatic sinusoidal endothelial cells (SEC) within 6 hours of HIR resulted in dehiscence of the SEC lining in 24 hours. Although there was no change of the number of Kupffer cells after HIR, colloidal carbon clearance decreased 24 hours post HIR, indicating a suppression of phagocytic function. DPPIV+ donor cells were transplanted 24 hours after HIR (0-50 Gy). There was an HIR dose-dependent increase in the donor hepatocyte mass engrafted in the liver parenchyma. The number of viable transplanted hepatocytes present in hepatic sinusoids or integrated in the parenchyma was greater in the HIR-treated group at 3 and 7 days after transplantation compared with the sham controls. Finally, we validated these rodent studies in cynomolgus monkeys, demonstrating that a single 10-Gy dose of HIR was sufficient to enhance engraftment of donor porcine hepatocytes. These data indicate that transient disruption of the SEC barrier and inhibition of the phagocytic function of Kupffer cells by HIR enhances hepatocyte engraftment and the integrated donor cell mass. Thus, preparative HIR could be potentially useful to augment hepatocyte transplantation.
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York 10467, USA.
authors.forename: Kosho
authors.initials: K
authors.lastname: Yamanouchi
authors.forename: Hongchao
authors.initials: H
authors.lastname: Zhou
authors.forename: Namita
authors.initials: N
authors.lastname: Roy-Chowdhury
authors.forename: Frank
authors.initials: F
authors.lastname: Macaluso
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Govardhana Rao
authors.initials: GR
authors.lastname: Yannam
authors.forename: Charles
authors.initials: C
authors.lastname: Enke
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Solberg
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Adelson
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Platt
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
authors.forename: Jayanta
authors.initials: J
authors.lastname: Roy-Chowdhury
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000528:radiation effects; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology; D005260:Female; D006085:Graft Survival; D006498:Hepatectomy; D022781:Hepatocytes / Q000528:radiation effects* / Q000637:transplantation*; D007728:Kupffer Cells / Q000502:physiology / Q000528:radiation effects; D008099:Liver / Q000166:cytology / Q000601:surgery*; D008115:Liver Regeneration / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D010587:Phagocytosis / Q000528:radiation effects; D051381:Rats; D011916:Rats, Inbred F344; D013552:Swine; D019172:Transplantation Conditioning / Q000379:methods; D014183:Transplantation, Heterologous
chemical_list: D018819:Dipeptidyl Peptidase 4