Bristol-Myers Squibb, Pennington, New Jersey.
Am J Physiol Gastrointest Liver Physiol. 2019 Jan 1;316(1):G15-G24. doi: 10.1152/ajpgi.00281.2018. Epub 2018 Nov 8.
Precision-cut liver tissue slice (PCLS) contains all major cell types of the liver parenchyma and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study liver fibrosis and test the antifibrotic effect of experimental compounds in a physiological environment. In this study using RNA sequencing, we demonstrated that various pathways functionally related to fibrotic mechanisms were dysregulated in PCLSs derived from rats subjected to bile duct ligation. The activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib each reversed a subset of genes dysregulated in fibrotic PCLSs, and of those genes we identified 608 genes whose expression was reversed by all three compounds. These genes define a molecular signature characterizing many aspects of liver fibrosis pathology and its attenuation in the model. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were further validated as efficacy end points for the evaluation of antifibrotic activity of experimental compounds. Finally, we showed that blockade of α-integrins with a small molecule inhibitor attenuated the fibrotic phenotype in the model. Overall, our results suggest that the rat fibrotic PCLS model may represent a valuable system for target validation and determining the efficacy of experimental compounds. NEW & NOTEWORTHY We investigated the antifibrotic activity of three compounds, the activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib, in a rat fibrotic precision-cut liver tissue slice model using RNA sequencing analysis. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were then established as efficacy end points to validate the antifibrotic activity of the α-integrin inhibitor CWHM12. This study demonstrated the value of the rat fibrotic PCLS model for the evaluation of antifibrotic drugs.
精密切割肝组织切片（PCLS）包含肝实质的所有主要细胞类型，并保留了原始的细胞-细胞和细胞-基质接触。它代表了一种很有前途的离体模型，可以在生理环境中研究肝纤维化，并测试实验化合物的抗纤维化作用。在这项使用 RNA 测序的研究中，我们证明了源自胆管结扎大鼠的 PCLS 中与纤维化机制相关的各种途径发生了功能失调。激活素受体样激酶-5（Alk5）抑制剂 SB525334、尼达尼布和索拉非尼均逆转了纤维化 PCLS 中失调的一部分基因，在这些基因中，我们鉴定出 608 个基因的表达被这三种化合物共同逆转。这些基因定义了一个分子特征，该特征表征了模型中肝纤维化病理及其衰减的许多方面。一组 12 个基因和 4 种分泌生物标志物，包括前胶原 I、透明质酸（HA）、胰岛素样生长因子结合蛋白 5（IGFBP5）和 WNT1 诱导信号通路蛋白 1（WISP1），进一步验证为评估实验化合物抗纤维化活性的疗效终点。最后，我们表明，用小分子抑制剂阻断α-整合素可减弱模型中的纤维化表型。总的来说，我们的结果表明，大鼠纤维化 PCLS 模型可能代表一个有价值的系统，可用于验证靶点和确定实验化合物的疗效。新的和值得注意的是，我们使用 RNA 测序分析研究了三种化合物，即激活素受体样激酶-5（Alk5）抑制剂 SB525334、尼达尼布和索拉非尼在大鼠纤维化精密切割肝组织切片模型中的抗纤维化活性。然后建立了一组 12 个基因和 4 种分泌生物标志物，包括前胶原 I、透明质酸（HA）、胰岛素样生长因子结合蛋白 5（IGFBP5）和 WNT1 诱导信号通路蛋白 1（WISP1），作为验证α-整合素抑制剂 CWHM12 的抗纤维化活性的疗效终点。这项研究证明了大鼠纤维化 PCLS 模型在评估抗纤维化药物方面的价值。
