Maintenance of Primary Hepatocyte Functions In Vitro by Inhibiting Mechanical Tension-Induced YAP Activation
Maintenance of Primary Hepatocyte Functions In Vitro by Inhibiting Mechanical Tension-Induced YAP Activation
复制标题
通过抑制机械张力诱导的 YAP 激活来维持体外原代肝细胞功能
DOI：
10.1016/j.celrep.2019.10.128
复制
发表时间：
2019-12-03
期刊：
影响因子：
8.8
通讯作者：
Li, Wenlin
中科院分区：
文献类型：
--
作者：
Sun, Pingxin;Zhang, Guanyu;Li, Wenlin
肝细胞是肝脏的主要功能细胞，执行其代谢、解毒和内分泌功能。功能性肝细胞在药物发现和评估以及肝脏疾病的细胞治疗中极其有价值。然而，在体外维持肝细胞的功能一直是一个长期的挑战。即使是新鲜分离的肝细胞在短期培养后也会失去基本功能，其原因尚不清楚。在本研究中，我们发现机械张力诱导的yes相关蛋白激活触发肝细胞去分化。通过限制细胞扩散来减轻机械张力足以抑制肝细胞去分化。基于这一发现，我们通过反复化学筛选确定了一种小分子混合物，可以通过靶向肌动蛋白聚合和肌动球蛋白收缩来长期维持肝细胞功能和体内再增殖能力。我们的工作揭示了肝细胞去分化的机制，并建立了维持肝细胞功能的可行方法。
Hepatocytes are the primary functional cells of the liver, performing its metabolic, detoxification, and endocrine functions. Functional hepatocytes are extremely valuable in drug discovery and evaluation, as well as in cell therapy for liver diseases. However, it has been a long-standing challenge to maintain the functions of hepatocytes in vitro. Even freshly isolated hepatocytes lose essential functions after short-term culture for reasons that are still not well understood. In the present study, we find that mechanical tension-induced yes-associated protein activation triggers hepatocyte dedifferentiation. Alleviation of mechanical tension by confining cell spreading is sufficient to inhibit hepatocyte dedifferentiation. Based on this finding, we identify a small molecular cocktail through reiterative chemical screening that can maintain hepatocyte functions over the long term and in vivo repopulation capacity by targeting actin polymerization and actomyosin contraction. Our work reveals the mechanisms underlying hepatocyte dedifferentiation and establishes feasible approaches to maintain hepatocyte functions.