A Pre-Clinical Large Animal Model of Sustained Liver Injury and Regeneration Stimulus

Abstract

A feasible large animal model to evaluate regenerative medicine techniques is vital for developing clinical applications. One such appropriate model could be to use retrorsine (RS) together with partial hepatectomy (PH). Here, we have developed the first porcine model using RS and PH. RS or saline control was administered intraperitoneally to Göttingen miniature pigs twice, two weeks apart. Four weeks after the second dose, animals underwent PH. Initially, we tested different doses of RS and resection of different amounts of liver, and selected 50 mg/kg RS with 60% hepatectomy as our model for further testing. Treated animals were sacrificed 3, 10, 17 or 28 days after PH. Blood samples and resected liver were collected. Serum and liver RS content was determined by Liquid Chromatograph-tandem Mass Spectrometer. Blood analyses demonstrated liver dysfunction after PH. Liver regeneration was significantly inhibited 10 and 17 days after PH in RS-treated animals, to the extent of 20%. Histological examination indicated hepatic injury and regenerative responses after PH. Immunohistochemical staining demonstrated accumulation of Cyclin D1 and suppression of Ki-67 and PCNA in RS-treated animals. We report the development of the first large animal model of sustained liver injury with suppression of hepatic regeneration.

Lipoparticles for Synergistic Chemo-Photodynamic Therapy to Ovarian Carcinoma Cells: In vitro and in vivo Assessments

“…The free THP treated group showed some signs of the apoptotic cells with fibrosis, pyknosis (condensation of nuclei due to apoptosis) and hepatic lesions. 66 No evidence of the necrotic bodies or hydrophobic degradation was found in any of the treatment groups. The kidney showed the signs of necrosis, apoptosis, as well as congestion of the renal tissue in the free THP and THP NP 200 nm, treated groups while other treatment groups remained unaffected.…”

Survival‐Assured Liver Injury Preconditioning (SALIC) Enables Robust Expansion of Human Hepatocytes in Fah–/–Rag2–/–IL2rg–/– Rats

“…Fah‐deficient rat and pig both developed acute liver failure after NTBC withdrawal [ 40 ] and were sensitive to retrorsine‐mediated inhibition of hepatocyte proliferation. [ 41 ] It may be worth testing whether the principle of SALIC could be applied to liver humanization in Fah –/– pigs. Furthermore, it would be interesting to propose SALIC as a useful reference for hepatocyte transplantation in human patients.…”

Sex-Dependent Effects on Liver Inflammation and Gut Microbial Dysbiosis After Continuous Developmental Exposure to Trichloroethylene in Autoimmune-Prone Mice

“…TCE-exposed females expressed high levels of proliferation and cell cycle markers, ki67 and cyclnd1 , relative to control females and males, regardless of TCE exposure. Like IL-6 related markers and chemokines/cytokines, KI67 and Cyclin D1 dysregulation is an indicator of many different liver conditions including hepatocellular carcinoma ( Salama et al, 2019 ), nonalcoholic fatty liver disease ( Dey et al, 2019 ), chronic alcohol exposure ( Chavez et al, 2011 ), and liver injury ( Inomata et al, 2018 ). The role of these proteins are not well described in AIH, however; experimentally-induced AIH had altered levels of these proliferation markers ( Huang et al, 2017 ).…”