Transcriptomic Analysis of Hepatic Cells in Multicellular Organotypic Liver Models.
Transcriptomic Analysis of Hepatic Cells in Multicellular Organotypic Liver Models.
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DOI：
10.1038/s41598-018-29455-x
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发表时间：
2018-07-27
影响因子：
4.6
通讯作者：
Rajagopalan P
中科院分区：
文献类型：
--
作者：
Tegge AN;Rodrigues RR;Larkin AL;Vu L;Murali TM;Rajagopalan P
肝脏稳态需要实质细胞和非实质细胞（npc）的存在。然而，肝脏的系统生物学研究主要集中在肝细胞上。利用器官型三维（3D）肝脏培养，我们首次报道了肝窦内皮细胞（LSECs）和库普弗细胞（KCs）与肝细胞培养的转录组学研究。通过计算途径和相互作用网络分析，我们证明肝细胞、LSECs和KCs具有不同的表达谱和功能特征。我们的研究结果表明，存在KCs的LSECs表现出局灶黏附激酶（FAK）信号的表达降低，这是与LSEC去分化相关的途径。我们报道了过氧化物酶体增殖物激活受体α (PPARα)在LSECs中转录的新结果。下游过程的表达证实了LSECs中活跃的PPARα信号传导。我们在LSECs中发现了PPARα和farnesoid x激活受体（FXR）之间的反馈机制的转录证据，该机制维持胆汁酸稳态；以前，这种反馈只发生在HepG2细胞中。我们证明，与单培养相比，3D肝脏模型中的KCs显示出与抗炎表型一致的表达模式。这些结果强调了LSECs和KCs在维持肝功能方面的独特作用，并强调了在模拟肝脏微环境中，除了肝细胞外，还需要对NPCs进行额外的机制研究。
Liver homeostasis requires the presence of both parenchymal and non-parenchymal cells (NPCs). However, systems biology studies of the liver have primarily focused on hepatocytes. Using an organotypic three-dimensional (3D) hepatic culture, we report the first transcriptomic study of liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) cultured with hepatocytes. Through computational pathway and interaction network analyses, we demonstrate that hepatocytes, LSECs and KCs have distinct expression profiles and functional characteristics. Our results show that LSECs in the presence of KCs exhibit decreased expression of focal adhesion kinase (FAK) signaling, a pathway linked to LSEC dedifferentiation. We report the novel result that peroxisome proliferator-activated receptor alpha (PPARα) is transcribed in LSECs. The expression of downstream processes corroborates active PPARα signaling in LSECs. We uncover transcriptional evidence in LSECs for a feedback mechanism between PPARα and farnesoid X-activated receptor (FXR) that maintains bile acid homeostasis; previously, this feedback was known occur only in HepG2 cells. We demonstrate that KCs in 3D liver models display expression patterns consistent with an anti-inflammatory phenotype when compared to monocultures. These results highlight the distinct roles of LSECs and KCs in maintaining liver function and emphasize the need for additional mechanistic studies of NPCs in addition to hepatocytes in liver-mimetic microenvironments.
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