A rat liver cell atlas reveals intrahepatic myeloid heterogeneity.

The large size and vascular accessibility of the laboratory rat (Rattus norvegicus) make it an ideal hepatic animal model for diseases that require surgical manipulation. Often, the disease susceptibility and outcomes of inflammatory pathologies vary significantly between strains. This study uses single-cell transcriptomics to better understand the complex cellular network of the rat liver, as well as to unravel the cellular and molecular sources of inter-strain hepatic variation. We generated single-cell and single-nucleus transcriptomic maps of the livers of healthy Dark Agouti and Lewis rat strains and developed a factor analysis-based bioinformatics analysis pipeline to study data covariates, such as strain and batch. Using this approach, we discovered transcriptomic variation within the hepatocyte and myeloid populations that underlie distinct cell states between rat strains. This finding will help provide a reference for future investigations on strain-dependent outcomes of surgical experiment models.

Reduced Complications after Arterial Reconnection in a Rat Model of Orthotopic Liver Transplantation.

The rat orthotopic liver transplantation (OLT) model is a powerful tool to study acute and chronic rejection. However, it is not a complete representation of human liver transplantation due to the absence of arterial reconnection. Described here is a modified transplantation procedure that includes the incorporation of hepatic artery (HA) reconnection, leading to a marked improvement in transplant outcomes. With a mean anhepatic time of 12 min and 14 s, HA reconnection results in improved perfusion of the transplanted liver and an increase in long-term recipient survival from 37.5% to 88.2%. This protocol includes the use of 3D-printed cuffs and holders to connect the portal vein and infrahepatic inferior vena cava. It can be implemented for studying multiple aspects of liver transplantation, from immune response and infection to technical aspects of the procedure. By incorporating a simple and practical method for arterial reconnection using a microvascular technique, this modified rat OLT protocol closely mimics aspects of human liver transplantation and will serve as a valuable and clinically relevant research model.

Nanoparticle Uptake in a Spontaneous and Immunocompetent Woodchuck Liver Cancer Model.

There is a tremendous focus on the application of nanomaterials for the treatment of cancer. Nonprimate models are conventionally used to assess the biomedical utility of nanomaterials. However, these animals often lack an intact immunological background, and the tumors in these animals do not develop spontaneously. We introduce a preclinical woodchuck hepatitis virus-induced liver cancer model as a platform for nanoparticle (NP)-based in vivo experiments. Liver cancer development in these out-bred animals occurs as a result of persistent viral infection, mimicking human hepatitis B virus-induced HCC development. We highlight how this model addresses key gaps associated with other commonly used tumor models. We employed this model to (1) track organ biodistribution of gold NPs after intravenous administration, (2) examine their subcellular localization in the liver, (3) determine clearance kinetics, and (4) characterize the identity of hepatic macrophages that take up NPs using RNA-sequencing (RNA-seq). We found that the liver and spleen were the primary sites of NP accumulation. Subcellular analyses revealed accumulation of NPs in the lysosomes of CD14+ cells. Through RNA-seq, we uncovered that immunosuppressive macrophages within the woodchuck liver are the major cell type that take up injected NPs. The woodchuck-HCC model has the potential to be an invaluable tool to examine NP-based immune modifiers that promote host anti-tumor immunity.

[Liver transplantation in end-stage liver disease with portal vein thrombosis].

OBJECTIVE: To summarize the experience in the managements of portal vein thrombosis (PVT) and to evaluate the impact of PVT on intraoperative course and postoperative outcome in liver transplantation. METHODS: Between May 1995 and September 2007, 194 orthotopic liver transplantations were performed, of which 24 cases presented portal vein thrombosis. There were 12 patients with grade I, 9 with grade II, 2 with grade III and 1 with grade IV. The management of PVT depended mainly on its extent. Ligation of the collateral circulation, especially spontaneous or surgical splenorenal shunt, was made as approaches to improve portal flow.Heparin or low-molecule-weight heparin as a prophylactic anticoagulation therapy was maintained during and after operation if prothrombin time is less than eighteen seconds. Follow-up Doppler ultrasonography was used daily in the early postoperative period. Risk factors and variables associated with the transplant and the post-transplant period were analyzed and compared with 170 patients transplanted without PVT. RESULTS: Surgical techniques were eversion thromboendovenectomy in 21 patients with PVT grades I and II, extra-anatomic mesenteric graft in 2 with grade III, and anastomosis to a collateral vein in 1 with grade IV. The study demonstrated more RBC transfusions [(15.2 +/- 11.8) U vs. (8.6 +/- 6.6) U, P = 0.006], longer surgery procedures [(492 +/- 89) min vs. (403 +/- 105) min, P = 0.001] and hospital stay [(32.4 +/- 13.5) d vs. (22.1 +/- 9.1) d, P = 0.001] in the PVT group. However, there were no differences in overall morbidity (58.3% vs. 50.6%, P = 0.478), hospital mortality (8.3% vs.6.5%, P = 0.73) and 1-year survival (87.5% vs. 89.4%, P = 0.778). The incidence of rethrombosis was higher in the PVT group (8.3% vs.1.2%, P = 0.021). Two cases rethrombosis were successfully cured by percutaneous thrombolysis, balloon angioplasty, and stent placement. CONCLUSION: Portal thrombosis is associated with greater operative complexity and rethrombosis, but has no influence on overall morbidity and mortality in liver transplantation.