sc-RNA sequencing data of primary liver cells from wildtype, YAPKO,TAZKO and DKO mice

Background & Aims The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are promising targets for cancer therapy. However, it is not understood if inhibition of one factor is compensated by the activation of the other and if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver-resident cells. Methods Mice with hepatocyte (HC)-/biliary epithelial cell (BEC)-specific deletions of YAP and/or TAZ were generated (YAPKO, TAZKO and double knock-out (DKO)). Liver tissues were investigated by histology, immunohistochemistry, and single cell RNA-sequencing (scRNA-seq). Serum samples were analyzed using a cytokine array. Results Liver tissues from YAPKO and DKO mice were characterized by the loss of BECs, liver fibrosis, and necrosis. This phenotype was weakened in DKO tissues compared to specimen from YAPKO animals. YAP expression was induced in different non-parenchymal cells (NPCs) after YAP-depletion in HCs and BECs. Activation of YAP in Kupffer cells (KCs) and endothelial cells (ECs) in subclusters with specific molecular features was independent of cholestasis. Pro-inflammatory chemokines and cytokines such as interleukin-1 (IL1) and intercellular adhesion molecule-1 (ICAM1) were detected in the serum of YAPKO animals. YAP-interacting TEA domain transcription factor (TEAD) family members bound promoter regions of different secreted factors and may contribute to a severe inflammatory response in mice with YAP-inactivation in HCs and BECs. Conclusions YAP inactivation causes severe liver damage in vivo and concomitant TAZ deletion does not enhance but moderately reduce this phenotype. Furthermore, we describe a new mechanism how YAP inactivation in HCs/BECs contributes to YAP-driven heterologous cell communication originating from NPCs. sc-RNA sequencing data were generared from primary liver cells of wildtype (n=1), YAPKO(n=1),TAZKO(n=1) and DKO (n=1) mice研究背景与目的：Hippo信号通路（Hippo pathway）及其转录效应因子Yes相关蛋白（YAP）与含PDZ结合基序的转录共激活因子（TAZ）是极具潜力的癌症治疗靶点。目前尚不明确抑制其中一个因子是否会通过激活另一个因子产生代偿效应，以及YAP/TAZ靶向扰动是否会影响非恶性肝脏驻留细胞的细胞间通讯。 研究方法：构建了肝细胞（HC）/胆管上皮细胞（BEC）特异性敲除YAP和/或TAZ的小鼠模型（分别为YAP敲除小鼠[YAPKO]、TAZ敲除小鼠[TAZKO]及双基因敲除小鼠[DKO]）。通过组织学、免疫组织化学及单细胞RNA测序（scRNA-seq）对肝脏组织进行检测分析，并采用细胞因子芯片对血清样本进行检测。 研究结果：YAPKO与DKO小鼠的肝脏组织以胆管上皮细胞缺失、肝纤维化及坏死为主要特征。与YAPKO小鼠的肝脏组织标本相比，DKO小鼠的该表型有所减轻。在肝细胞与胆管上皮细胞的YAP被敲除后，多种非实质细胞（NPCs）中的YAP表达被诱导上调。具有特定分子特征的亚群库普弗细胞（KCs）与内皮细胞（ECs）中的YAP激活与胆汁淤积无关。YAPKO小鼠的血清中可检测到促炎性趋化因子与细胞因子，如白细胞介素-1（IL1）及细胞间黏附分子-1（ICAM1）。与YAP相互作用的TEA结构域转录因子（TEAD）家族成员可结合多种分泌因子的启动子区域，可能在肝细胞与胆管上皮细胞YAP失活的小鼠中参与介导严重炎症反应。 研究结论：YAP失活可在体内引发严重肝损伤，而同时敲除TAZ并不会加重该表型，反而会轻度减轻其严重程度。此外，本研究揭示了一种全新机制：肝细胞/胆管上皮细胞的YAP失活如何促进源于非实质细胞的YAP介导的异源细胞通讯。本研究的单细胞RNA测序数据来源于野生型（n=1）、YAPKO（n=1）、TAZKO（n=1）及DKO（n=1）小鼠的原代肝脏细胞。