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Additional Supporting Information may be found in the online version of this article.

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HEP_26335_sm_SuppFig1.tif10732KSupporting Information Figure 1. Extensive bile duct proliferation and portal inflammation in the livers of Mdr2-KO mice at young age. (A) H&E staining of representative liver sections from Mdr2+/-/FVB, Mdr2-KO/FVB, Mdr2+/-/B6, and Mdr2-KO/B6 mice aged one (upper panels), two (middle panels) or three (bottom panels) months. Magnification x100. (B) F4/80 immunostaining for Mdr2-KO and control mice of both strains. Animal age and image magnification are as in (A). Higher F4/80 expression reflects higher infiltration of the monocytes/macrophages into Mdr2-KO compared to control Mdr2+/- livers starting from the first month of age. (C, D) Kinetics of T cells (C) and neutrophils (D) infiltration into the Mdr2-KO/FVB and Mdr2-KO/B6 livers. Staining with CD3-specific antibody reveals intense infiltration of T cells into portal tracts of the Mdr2-KO/FVB (left panel), and Mdr2-KO/B6 (right panel) livers. Staining with Ly-6B-specific antibody reveals intense infiltration of neutrophils into portal tracts of the Mdr2-KO/FVB (left panel), and Mdr2-KO/B6 livers (right panel). There was no T cell and neutrophil infiltration into the control livers (data not shown); animal age and image magnification – as in (A).
HEP_26335_sm_SuppFig2.tif4926KSupporting Information Figure 2. Higher BrdU incorporation into hepatocytes of Mdr2-KO mice compared to Mdr2+/- controls in both strains at early age. (A) BrdU incorporation in Mdr2+/- (top row), and Mdr2-KO (bottom row) livers of the FVB strain. (B) BrdU incorporation in Mdr2+/+ (top row), Mdr2+/- (middle row) and Mdr2-KO (bottom row) livers of the B6 strain. Magnification x100. For each group, four to eight mice were used at each time point.
HEP_26335_sm_SuppFig3.tif8372KSupporting Information Figure 3. Cyclin D1 is over-expressed in hepatocyte nuclei of Mdr2-KO mice of both strains. Liver tissue sections obtained from Mdr2-KO and control Mdr2+/- mice of the FVB (A) and B6 (B) strains were analyzed at the age of 1, 2 and 3 months and stained with the anti-cyclin D1 antibody. Magnification x100.
HEP_26335_sm_SuppFig4.tif7155KSupporting Information Figure 4. Rare apoptotic events of non-hepatic cells from control and mutant livers. TUNEL assay was performed on Mdr2+/-/FVB and Mdr2-KO/FVB liver sections to label apoptotic cells; cell nuclei were stained with DAPI (magnification x400). Left panel: TUNEL staining; middle panel: DAPI staining; right panel: overlay of both stainings. In the first month of age, an increased apoptosis of non-hepatic cells in the mutant livers was detected.
HEP_26335_sm_SuppFig5.tif6526KSupporting Information Figure 5. Expression of the Lipin-1 and Mbd1 proteins in the liver tumors of aged Mdr2-KO mice. IHC staining of the tumor (T) and non-tumor (NT) liver tissues from Mdr2-KO mice of the B6 (A, C) and FVB (B, D) genetic backgrounds. (A, B) Lipin-1 expression; (C, D) Mbd-1 expression. Mdr2-KO/B6 mice were 18 months-old, Mdr2-KO/FVB mice were 14 months-old. The different patterns of staining - higher in T compared to NT (left panel) or equal, or less in T compared to NT (right panel) - are presented for each strain. Magnification x100. Arrowheads show borders between T and NT tissues.
HEP_26335_sm_SuppTab1.doc12KSupporting Information Table 1. PCR primers used in this study.
HEP_26335_sm_SuppTab2.doc39KSupporting Information Table 2. Selected genes aberrantly expressed in the Mdr2-KO livers of only one of the FVB or B6 strains.
HEP_26335_sm_SuppTab3.doc33KSupporting Information Table 3. Selected genes aberrantly expressed in the Mdr2-KO livers of both FVB and B6 strains.
HEP_26335_sm_SuppTab4.doc66KSupporting Information Table 4. Known genotypic and phenotypic differences between FVB and B6 strains.
HEP_26335_SuppInfo.docx28KSupporting Information.

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