Liver slices as a model to study fibrogenesis and test the effects of anti-fibrotic drugs on fibrogenic cells in human liver.
Cell culture models have contributed significantly to the study of liver fibrosis, but cannot accurately incorporate in vivo cell-cell and cell-extracellular matrix interactions or account for the heterogeneity of the fibrogenic cell population involved in fibrosis development. Thus, there persists a need for an in vitro model that mimics the in vivo situation more closely, which may be provided by using precision-cut liver slices. In the present study we evaluated human liver slices as a tool to study fibrogenesis and test anti-fibrotic drugs. In this study we examined the responses of fibrogenic cells in human liver slices during control incubation and studied the effect of the anti-fibrotic compound pentoxifylline both during control incubation and after induction of early hepatic stellate cell (HSC) activation by carbon tetrachloride. After prolonged (>24 h) incubation, alphaSMA and pro-collagen 1a1 mRNA expression in human liver slices started to increase. Analysis of synaptophysin and fibulin-2 mRNA expression indicated that both activated HSC and other (myo)fibroblasts may be involved in this process. This response of fibrogenic cells to prolonged incubation of the liver slices was accompanied by an increased collagen protein content and could be inhibited by pentoxifylline. Early HSC activation, which was reflected by increased HSP47 and alphaB-crystallin mRNA expression, was not inhibited by pentoxifylline. Preparation and/or culturing of human liver slices induces fibrogenesis, which may be mediated by both activated HSC and resident liver (myo)fibroblasts and may represent a simple and rapid method to test the effects of potential anti-fibrotic drugs on fibrogenic cells in human liver.
van de Bovenkamp
M
M
Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Groothuis
G M M
GM
Meijer
D K F
DK
Olinga
P
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology / Q000517:prevention & control; D048430:Cell Shape; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D003094:Collagen; D010431:Pentoxifylline