Abstract
Mechanisms directing position-specific liver gene regulation are incompletely understood. To establish whether this aspect of hepatic gene expression is an inveterate phenomenon, we used transplanted hepatocytes as reporters in dipeptidyl peptidase IV-deficient F344 rats. After integration in liver parenchyma, the position of transplanted cells was shifted from periportal to perivenous areas by targeted hepatic ablations with carbon tetrachloride. In controls, transplanted cells showed greater glucose-6-phosphatase and lesser glycogen content in periportal areas. This pattern was reversed when transplanted cells shifted from periportal to perivenous areas. Transplanted hepatocytes in perivenous areas exhibited inducible cytochrome P450 activity, which was deficient in periportal hepatocytes. Moreover, cytochrome P450 activity was rapidly extinguished in activated hepatocytes when these cells were transplanted into the nonpermissive liver of suckling rat pups. In cells isolated from the normal F344 rat liver, cytochrome P450 inducibility was originally greater in perivenous hepatocytes; however, periportal cells rapidly acquired this facility in culture conditions. These findings indicate that the liver microenvironment exerts supremacy over prior differentiation state of cells in directing position-specific gene expression. Therefore, persistence of specialized hepatocellular function will require interactions with regulatory signals and substrate availability, which bears upon further analysis of liver gene regulation, including in progenitor and/or stem cells.
Highlights
Hepatocytes show unique differences in gene expression patterns in the liver lobule
Hepatocyte subsets, including those involved in drug disposition in perivenous areas, led to speculations concerning the presence of less differentiated hepatic progenitor cells in periportal areas with less comprehensive gene expression repertoire, followed by the acquisition of specialized functions in more differentiated hepatocytes in perivenous areas [12]
At 24 months, transplanted hepatocytes showed somewhat larger cell clusters in F344 rats, which indicated the possibility of spontaneous cell proliferation in this setting, transplanted cells still remained in periportal locations
Summary
Animals—Eight- to 10-week old DPPIVϪ F344 rats weighing 160 – 180 g and 3-day-old DPPIVϪ pups weighing 7–9 g were provided by the Special Animal Core of the Marion Bessin Liver Research Center. Histological Analysis for Transplanted Cell Localization—To localize F344 rat hepatocytes in DPPIVϪ animals, histochemical staining was performed on frozen tissue sections as reported previously [15]. To document the position of transplanted cells in tissues, serial wedge liver biopsies were obtained from individual CCl4-treated adult rats. Glu-6-P activity was determined in unfixed cryostat tissue, followed by acetonechloroform fixation and DPPIV histochemistry for localizing transplanted cells, as described previously [15]. The other animal group was given three doses of CCl4 at 10-day intervals to cause perivenous injury and shift the position of transplanted hepatocytes from periportal to perivenous areas during the ensuing liver repair (Fig. 1A). A second experiment concerned transplantation of hepatocytes into suckling DPPIVϪ rat pups with P450 induction by treating the donor rat with phenobarbitone for 7 days. The significance of differences was analyzed as appropriate by Student’s t test, Chi-square test, Mann-Whitney rank sum tests, or analysis of variance
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