Charité Universitätsmedizin Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Berlin, Germany; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Berlin Institute of Health, Center for Regenerative Therapies (BCRT), Berlin, Germany; Berlin Institute of Health, Clinician-Scientist Program, Berlin, Germany.
Berlin Institute of Health, Center for Regenerative Therapies (BCRT), Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany.
Cell Mol Gastroenterol Hepatol. 2023;15(5):1135-1145. doi: 10.1016/j.jcmgh.2023.01.014. Epub 2023 Feb 3.
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting multiple cell types of the human liver. The high prevalence of NAFLD and the lack of approved therapies increase the demand for reliable models for the preclinical discovery of drug targets. In the last decade, multiple proof-of-principle studies have demonstrated human-specific NAFLD modeling in the dish. These systems have included technologies based on human induced pluripotent stem cell derivatives, liver tissue section cultures, intrahepatic cholangiocyte organoids, and liver-on-a-chip. These platforms differ in functional maturity, multicellularity, scalability, and spatial organization. Identifying an appropriate model for a specific NAFLD-related research question is challenging. Therefore, we review different platforms for their strengths and limitations in modeling NAFLD. To define the fidelity of the current human in vitro NAFLD models in depth, we define disease hallmarks within the NAFLD spectrum that range from steatosis to severe fibroinflammatory tissue injury. We discuss how the most common methods are efficacious in modeling genetic contributions and aspects of the early NAFLD-related tissue response. We also highlight the shortcoming of current models to recapitulate the complexity of inter-organ crosstalk and the chronic process of liver fibrosis-to-cirrhosis that usually takes decades in patients. Importantly, we provide methodological overviews and discuss implementation hurdles (eg, reproducibility or costs) to help choose the most appropriate NAFLD model for the individual research focus: hepatocyte injury, ductular reaction, cellular crosstalk, or other applications. In sum, we highlight current strategies and deficiencies to model NAFLD in the dish and propose a framework for the next generation of human-specific investigations.
非酒精性脂肪性肝病 (NAFLD) 是一种影响人类肝脏多种细胞类型的慢性肝脏疾病。NAFLD 的高患病率和缺乏批准的治疗方法增加了对药物靶点临床前发现的可靠模型的需求。在过去的十年中，多项原理验证研究已经证明了在体外能够构建人类特异性的 NAFLD 模型。这些系统包括基于人类诱导多能干细胞衍生的技术、肝组织切片培养、肝内胆管细胞类器官和芯片上肝脏。这些平台在功能成熟度、多细胞性、可扩展性和空间组织方面存在差异。确定用于特定 NAFLD 相关研究问题的合适模型具有挑战性。因此，我们综述了不同平台在建模 NAFLD 方面的优缺点。为了深入了解当前人类体外 NAFLD 模型的保真度，我们定义了 NAFLD 谱内的疾病特征，范围从脂肪变性到严重的纤维炎症组织损伤。我们讨论了最常见的方法如何有效地模拟遗传贡献和与 NAFLD 相关的早期组织反应的各个方面。我们还强调了当前模型无法重现器官间串扰和肝脏纤维化到肝硬化的慢性过程的复杂性，而在患者中通常需要几十年的时间。重要的是，我们提供了方法概述，并讨论了实施障碍（例如，可重复性或成本），以帮助根据个人研究重点选择最合适的 NAFLD 模型：肝细胞损伤、胆管反应、细胞串扰或其他应用。总之，我们强调了当前在体外模拟 NAFLD 的策略和不足，并提出了下一代人类特异性研究的框架。
