Human Nonalcoholic Steatohepatitis on a Chip.
Human Nonalcoholic Steatohepatitis on a Chip.
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DOI：
10.1002/hep4.1647
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发表时间：
2021-03
影响因子：
5.1
通讯作者：
Jang HL
中科院分区：
文献类型：
--
作者：
Freag MS;Namgung B;Reyna Fernandez ME;Gherardi E;Sengupta S;Jang HL
我们开发了一种NASH芯片，其中人原代肝细胞（HC），Kupffer细胞（KC）和肝星状细胞（HSC）在3D水凝胶支架中培养，而血管模拟内皮化入口通道使用人肝窦内皮细胞（LSEC）进行工程化，通过该系统暴露于代谢和炎症应激源。将肝芯片暴露于脂毒性环境导致NASH表型特征的逐渐发展，包括细胞内脂质积聚、肝细胞气球样变、HSC活化以及炎症和促纤维化分子标志物的升高。我们证明，NASH芯片可用于测试药物抑制NASH发展的功效。 非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病（NAFLD）的晚期，是一个快速增长的全球性健康问题，目前缺乏特异性治疗。开发新的NASH疗法的主要限制因素是缺乏捕获肝脏微环境的独特细胞结构并概括NAFLD进展为NASH的复杂性的模型。芯片上器官平台已成为动态建模疾病和测试药物的强大方法。在此，我们描述了一种NASH芯片平台。四种主要类型的人原代肝细胞（肝细胞[HC]，枯否细胞，肝窦内皮细胞和肝星状细胞[HSC]）在微流体动力学下共培养。我们的基于芯片的模型成功地重现了功能性肝细胞微环境，具有稳定的白蛋白和尿素分泌至少2周。将肝芯片暴露于脂毒性环境导致NASH表型特征的逐渐发展，包括细胞内脂质积聚、肝细胞气球样变、HSC活化以及炎症和促纤维化标志物的升高。此外，将芯片暴露于正在研究的用于治疗NASH的药物elafibranor，可抑制NASH特异性标志物的发展，导致细胞内脂质减少约8倍，气球样HC数量减少3倍，HSC活化显著减少，炎症和促纤维化标志物水平显著降低。结论：我们已经成功开发了一种微流体NASH芯片平台，该平台在单个芯片中概括了主要的NASH组织学终点，并且可以作为一种强大的非侵入性，人类相关的体外平台来研究疾病发病机制并开发新型抗NASH药物。
We developed a NASH‐on‐a‐chip where human primary hepatocytes (HCs), Kupffer cells (KCs), and hepatic stellate cells (HSCs) were cultured in the 3D hydrogel scaffold, while a blood vessel mimetic endothelialized inlet channel was engineered using human liver sinusoidal endothelial cells (LSECs), via which the system was exposed to metabolic and inflammatory stressors. Exposing liver chips to a lipotoxic environment led to the gradual development of NASH phenotypic characteristics, including intracellular lipids accumulation, hepatocellular ballooning, HSC activation, and elevation of inflammatory and profibrotic molecular markers. We demonstrate that the NASH‐on‐a‐chip can be used to test the efficacy of pharmacological agents to inhibit the development of NASH. Nonalcoholic steatohepatitis (NASH), an advanced stage of nonalcoholic fatty liver disease (NAFLD), is a rapidly growing and global health problem compounded by the current absence of specific treatments. A major limiting factor in the development of new NASH therapies is the absence of models that capture the unique cellular structure of the liver microenvironment and recapitulate the complexities of NAFLD progression to NASH. Organ‐on‐a‐chip platforms have emerged as a powerful approach to dynamically model diseases and test drugs. Herein, we describe a NASH‐on‐a‐chip platform. Four main types of human primary liver cells (hepatocytes [HCs], Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells [HSCs]) were cocultured under microfluidic dynamics. Our chip‐based model successfully recapitulated a functional liver cellular microenvironment with stable albumin and urea secretion for at least 2 weeks. Exposing liver chips to a lipotoxic environment led to gradual development of NASH phenotypic characteristics, including intracellular lipid accumulation, hepatocellular ballooning, HSC activation, and elevation of inflammatory and profibrotic markers. Further, exposure of the chip to elafibranor, a drug under study for the therapy of NASH, inhibited the development of NASH‐specific hallmarks, causing an ~8‐fold decrease in intracellular lipids, a 3‐fold reduction in number of ballooned HCs, a significant reduction in HSC activation, and a significant decrease in the levels of inflammatory and profibrotic markers compared with controls. Conclusion: We have successfully developed a microfluidic NASH‐on‐a‐chip platform that recapitulates the main NASH histologic endpoints in a single chip and that can emerge as a powerful noninvasive, human‐relevant, in vitro platform to study disease pathogenesis and develop novel anti‐NASH drugs.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
25.7
作者：
Gandhi CR
通讯作者：
Gandhi CR
影响因子：
3.7
作者：
Gori M;Simonelli MC;Giannitelli SM;Businaro L;Trombetta M;Rainer A
通讯作者：
Rainer A
影响因子：
9.3
作者：
Boeckmans, Joost;Buyl, Karolien;Vanhaecke, Tamara
通讯作者：
Vanhaecke, Tamara
影响因子：
6.1
作者：
Esch MB;Prot JM;Wang YI;Miller P;Llamas-Vidales JR;Naughton BA;Applegate DR;Shuler ML
通讯作者：
Shuler ML