Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Mol Cell. 2019 Aug 8;75(3):644-660.e5. doi: 10.1016/j.molcel.2019.07.028.
Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.
细胞间通过配体-受体信号传递的通讯是复杂器官的基本特征。尽管如此，哺乳动物肝脏中细胞间信号的全局图景尚未阐明。在这里，我们对从健康和 NASH 小鼠肝脏中分离的非实质细胞进行了单细胞 RNA 测序。分泌组基因分析显示，NASH 中存在高度连接的肝内信号网络和血管信号中断。我们发现了与 NASH 相关的巨噬细胞 (NAMs) 的出现，它们的特征是表达在髓细胞上的触发受体 2 (Trem2) 的高表达，这是小鼠和人类 NASH 的一个特征，与疾病严重程度相关，并且对药理学和饮食干预高度敏感。最后，肝星状细胞 (HSCs) 通过 HSC 衍生的 stellakines 及其对血管活性激素的反应性，充当肝内信号传递的枢纽。这些结果提供了对健康和疾病状态下细胞间串扰和肝脏细胞重编程的景观的前所未有的见解。
