A Human Liver-on-a-Chip Platform for Modeling Nonalcoholic Fatty Liver Disease
A Human Liver-on-a-Chip Platform for Modeling Nonalcoholic Fatty Liver Disease
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DOI：
10.1002/adbi.201900104
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发表时间：
2019-08-01
影响因子：
4.1
通讯作者：
Khademhosseini, Ali
中科院分区：
文献类型：
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作者：
Lasli, Soufian;Kim, Hon-Jun;Khademhosseini, Ali
肝脏具有独特的微环境，具有复杂的内部血管系统和细胞-细胞相互作用。非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，尽管已经有很多研究致力于建立针对NAFLD的模型，但大多数体外系统依赖于简单的模型，无法重现复杂的肝功能。本研究提出了一个体外系统，通过将人肝细胞癌（HepG2）细胞和脐静脉内皮细胞（HUVECs）共培养成球体来研究NAFLD（脂肪变性）。对HepG2- huvec的共定位与脂肪变性水平的分析表明，当20%的huvec出现在HepG2球体中时，NAFLD的发病机制可以更好地建模。添加脂肪的球状体在第2天进入脂肪变性阶段，可以维持一周以上而不会对细胞造成伤害。将球体转移到具有一系列相互连接的六边形微孔的芯片系统上，通过HepG2-HUVEC相互作用增加白蛋白分泌和脂肪变性球体活性氧的产生增加，证明有助于监测功能。脂肪变性的可逆性可以通过停止以脂肪为基础的饮食或服用抗脂肪变性药物来证明，后者显示细胞内脂质水平更快地恢复到基础水平。
The liver possesses a unique microenvironment with a complex internal vascular system and cell-cell interactions. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, and although much effort has been dedicated to building models to target NAFLD, most in vitro systems rely on simple models failing to recapitulate complex liver functions. Here, an in vitro system is presented to study NAFLD (steatosis) by coculturing human hepatocellular carcinoma (HepG2) cells and umbilical vein endothelial cells (HUVECs) into spheroids. Analysis of colocalization of HepG2-HUVECs along with the level of steatosis reveals that the NAFLD pathogenesis could be better modeled when 20% of HUVECs are presented in HepG2 spheroids. Spheroids with fat supplements progressed to the steatosis stage on day 2, which could be maintained for more than a week without being harmful for cells. Transferring spheroids onto a chip system with an array of interconnected hexagonal microwells proves helpful for monitoring functionality through increased albumin secretions with HepG2-HUVEC interactions and elevated production of reactive oxygen species for steatotic spheroids. The reversibility of steatosis is demonstrated by simply stopping fat-based diet or by antisteatotic drug administration, the latter showing a faster return of intracellular lipid levels to the basal level.