Fig 1: FAP expression in CCl4and Mdr2−/− fibrotic livers with/without FAP inhibition and effect of rhFAP/rmFAP on LX-2 HSCs and murine fibroblasts. (A–B), Transcript levels of fap. (C–D), Effect of treatment with rhFAP on LX2 HSCs activation and collagen gene expression. (E–F), Effect of treatment with rmFAP on NIH/3T3 fibroblast activation and collagen gene expression. Data in (A–F) are means ± standard error of the means (SEMs). Statistical analysis was performed as detailed in Figure 1.
Fig 2: FAP inhibition does not modify T cell infiltration and suppresses cell proliferation in Mdr2−/− mice. (A–C), Representative images and quantification of CD3- and Ki67-positive cells in 10 random fields (×200) from the central right lobe of each liver. Data in (B–C) are means ± standard error of the means (SEMs). Statistical analysis was performed as detailed in Figure 1.
Fig 3: Effect of FAP inhibition on liver/spleen weight and general liver inflammation in Mdr2−/− mice. (A), Scheme of FVB control and Mdr2−/− biliary fibrotic mice (n = 5 and n = 10 mice per group, respectively) treated with FAPi (15 or 50 mg/kg bw) or vehicle for 2 weeks. (B−C), Liver/bw ratio and spleen/bw ratio. (D), Representative images of H&E staining from liver sections. (E−H), Serum ALT, AST, ALP, and creatinine levels. Data in (B−C, E−H) are means ± standard errors of the mean (SEMs). Statistical analysis was performed as for Figure 1.
Fig 4: Treatment of CCl4-fibrotic mice with FAP inhibitor. (A), Scheme of experimental design. Female C56BL/6 mice received escalating doses of oral CCl4 in mineral oil (fibrotic group, n = 10) or mineral oil alone (non-fibrotic controls, n = 5) for 6 weeks. Fibrotic mice were analyzed at peak progression or after 2 weeks of regression. Other groups of fibrotic mice continued with their chow were set on chow containing FAPi at 15 or 50 mg/kg/d (n = 10 per group). (B–C), Liver/bw ratio and spleen/bw ratios. (D), Representative images of H&E-stained liver section of each group. (E–H), Serum ALT, AST, ALP, and creatinine levels. Data in (B–C, E–H) are presented as means ± standard error of the mean (SEM). Statistical analysis was performed by 1-way analysis of variance followed by Tukey’s post hoc test (∗P < .05; ∗∗P < .01; ∗∗∗P < .005; ns, not significant).
Fig 5: FAP inhibition attenuates parenchymal liver fibrosis. (A–C), Livers of mice (n = 5–10/group) treated with FAPi during fibrosis progression or regression vs fibrotic untreated controls were analyzed by quantitative Sirius red and α-SMA immunohistochemistry, performed in 10 random high-power fields per mouse using ImageJ software. (D), Histological fibrosis score of liver sections. (E–F), Hepatic hydroxyproline concentration. (G), Hepatic transcript of fibrosis related transcripts. Data in (B–G) are means ± standard error of the means (SEMs). Statistical analysis was performed as for Figure 1.
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