Fig. 8

Use of TGFβ inhibitors in vivo impairs transmission of paracrine senescence and improves liver function. a Pattern of administration of LY2157299 by oral gavage after induction of senescence in the K19-Mdm2^flox/floxtdTom^LSL model. b Representative images of p21 (red) in cholangiocytes (green) in mice treated with vehicle, 10 or 20 mg/kg of LY2157299. c Percentage of p21-positive cholangiocytes diminishes with the administration of LY2157299. d Total percentage of p21 diminishes with LY2157299 administration. e Decrease of p27 total number of cells with LY2157299 administration. f Percentage of tdTom-positive cholangiocytes is not altered. Statistic analysis for c–f * denotes p < 0.05, ** denotes p < 0.01, *** denotes p < 0.001, **** denotes p < 0.0001 (Mean ± SEM). ANOVA, Sidak’s multiple comparisons test (N = 5 per group). g After induction of senescence in cholangiocytes, LY2157299 was administered to the mice by oral gavage. Then DDC diet was administered to the mice for 1 week. Experimental groups for this experiment include: Senescence + Vehicle + DDC (Veh, N = 5) and Senescence + Inhibitor + DDC (Inh, N = 5). h Decrease in serum transaminase levels. i Increased levels of Ki67-positive cholangiocytes with the use of LY2157299. Far right, quantification. j Increased levels of total Ki67 per field with LY2157299. k Trend to decrease (p = 0.0952) of total p27 levels. l Left, decreased expression of p21-positive hepatocytes. Right, decreased expression of p16-positive hepatocytes. m Decreased collagen deposition with the use of LY2157299. n Trend to decrease (p = 0.1508) of total number of F4/80 macrophages per field. * denotes p < 0.05, ** p < 0.01 (Mean ± SEM). Student’s ttest. Scale bars = 50 µm