Department of Surgery, Division of Transplant Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana.
Semin Liver Dis. 2022 Nov;42(4):423-433. doi: 10.1055/a-1934-5588. Epub 2022 Aug 31.
Despite the rising prevalence of nonalcoholic fatty liver disease (NAFLD), the underlying disease pathophysiology remains unclear. There is a great need for an efficient and reliable "human" in vitro model to study NAFLD and the progression to nonalcoholic steatohepatitis (NASH), which will soon become the leading indication for liver transplantation. Here, we review the recent developments in the use of three-dimensional (3D) liver organoids as a model to study NAFLD and NASH pathophysiology and possible treatments. Various techniques that are currently used to make liver organoids are discussed, such as the use of induced pluripotent stem cells versus primary cell lines and human versus murine cells. Moreover, methods for inducing lipid droplet accumulation and fibrosis to model NAFLD are explored. Finally, the limitations specific to the 3D organoid model for NAFLD/NASH are reviewed, highlighting the need for further development of multilineage models to include hepatic nonparenchymal cells and immune cells. The ultimate goal is to be able to accurately recapitulate the complex liver microenvironment in which NAFLD develops and progresses to NASH.
尽管非酒精性脂肪性肝病 (NAFLD) 的患病率不断上升，但该病的发病机制仍不清楚。因此，非常需要一种高效、可靠的“人类”体外模型来研究 NAFLD 及其向非酒精性脂肪性肝炎 (NASH) 的进展，NASH 很快将成为肝移植的主要适应证。本文综述了近年来利用三维 (3D) 肝类器官作为研究 NAFLD 和 NASH 发病机制及可能治疗方法的模型的最新进展。讨论了目前用于制作肝类器官的各种技术，例如使用诱导多能干细胞与原代细胞系和人源细胞与鼠源细胞。此外，还探索了用于模拟 NAFLD 的脂滴积累和纤维化的方法。最后，本文还综述了 3D 类器官模型在 NAFLD/NASH 研究中的局限性，并强调需要进一步开发多谱系模型以纳入肝非实质细胞和免疫细胞。最终目标是能够准确再现 NAFLD 发生和进展为 NASH 的复杂肝脏微环境。
