title: Serum apolipoprotein E as a marker to monitor graft function after hepatocyte transplantation in a clinically relevant mouse model.
abstract: BACKGROUND
  Hepatocyte transplantation, a promising treatment for patients with acute hepatic failure or metabolic liver diseases, requires improvement in engraftment as well as long-term function of the liver cells. We established a hepatocyte transplantation model in apolipoprotein E (ApoE) knockout mice, evaluating serum ApoE and lipoprotein profiles as markers of engraftment of transplanted wild-type hepatocytes. Herein we have described a method to monitor the function of transplanted hepatocytes at low levels of engraftment, corresponding to those reported in clinical cases. We also investigated whether pretreatment with anakinra, an anti-interleukin-1 antagonist, methylprednisolone, or a combination of the two agents improved engraftment.
  
  
  METHODS
  ApoE (-/-) mice were transplanted with hepatocytes isolated from wild-type C57/bl6 mice. A total of 6 × 10(6) hepatocytes were transplanted by 3 separate intrasplenic injections. Animals were treated before transplantation and daily thereafter for 7 days with anakinra, methylprednisolone, or a combination of both. Graft function was monitored by lipoprotein analysis and quantification of ApoE by enzyme-linked immunosorbent assay. Expression of hepatic ApoE mRNA was quantitated by reverse-transcriptase polymerase chain reaction.
  
  
  RESULTS
  Treatment with anakinra with or without methylprednisolone did not significantly increase serum or hepatic mRNA ApoE expression. The low level of hepatocyte engraftment did not normalize lipoprotein profiles, but produced a significant decline in very low-density lipoprotein and total cholesterol. Repeated transplantations significantly enhanced liver repopulation; serum ApoE levels increased with each infusion, correlating well with hepatic mRNA expression.
  
  
  CONCLUSIONS
  The model of serum ApoE, a sensitive marker of engraftment and transplanted hepatocyte function, allowed us to study hepatocyte transplantation in a clinically relevant manner, that is, without pretreatments such as retrorsine or carbon tetrachloride.
authors.affiliation: Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. carl.jorns@ki.se
authors.forename: C
authors.initials: C
authors.lastname: Jorns
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: E
authors.initials: E
authors.lastname: Callaghan
authors.forename: H
authors.initials: H
authors.lastname: Zemack
authors.forename: L
authors.initials: L
authors.lastname: Larsson
authors.forename: G
authors.initials: G
authors.lastname: Nowak
authors.forename: P
authors.initials: P
authors.lastname: Parini
authors.forename: B-G
authors.initials: BG
authors.lastname: Ericzon
authors.forename: E
authors.initials: E
authors.lastname: Ellis
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000097:blood* / Q000235:genetics; D015415:Biomarkers / Q000097:blood*; D002784:Cholesterol / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D022781:Hepatocytes / Q000637:transplantation*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D012333:RNA, Messenger; D002784:Cholesterol