美国辛辛那提儿童医院医疗中心Takanori Takebe课题组牵头的国际联合研究团队发现能够用多能干细胞衍生器官模拟人类脂肪性肝炎。相关论文于2019年8月发表于国际顶尖学术期刊之一的《细胞—代谢》杂志上。

该联合研究团队使用了11种不同健康和患病的多能干细胞系，开发出一种可重复的方法来获得由肝细胞，星状细胞和库普弗样细胞组成的多细胞人肝脏类器官，这些细胞表现出与体内衍生组织的转录组学相似性。在游离脂肪酸治疗下，非重组共培养的类脂质细胞，以连续的方式概括出现了脂肪性肝炎的主要特征，包括脂肪变性、炎症和纤维化表型。有趣的是，原子力显微镜观察这种类器官级的生物物理学数据表明，器官硬化反映了纤维化的严重程度。此外，来自患有溶酶体酸性脂肪酶遗传功能障碍的患者的类器官表达了严重的脂肪性肝炎，他们可以通过FXR激动介导的活性氧物质抑制来救治。该研究所提出的关键方法和初步实验结果为人类炎症和纤维化的个性化研究提供了研究基础，有助于未来发现有效的治疗方法。

研究人员表示，人体的类器官系统在体内重复了器官结构，但未能捕获复杂的病理情况，如炎症和纤维化。

附：英文原文

Title: Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids

Author: Rie Ouchi, Shodai Togo, Masaki Kimura, Hiroshi Y. Yoshikawa, James M. Wells, Takanori Takebe

Issue&Volume: Volume 30 Issue 2

Abstract: Human organoid systems recapitulate in vivo organ architecture yet fail to capture complex pathologies such as inflammation and fibrosis. Here, using 11 different healthy and diseased pluripotent stem cell lines, we developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues. Under free fatty acid treatment, organoids, but not reaggregated cocultured spheroids, recapitulated key features of steatohepatitis, including steatosis, inflammation, and fibrosis phenotypes in a successive manner. Interestingly, an organoid-level biophysical readout with atomic force microscopy demonstrated that organoid stiffening reflects the fibrosis severity. Furthermore, organoids from patients with genetic dysfunction of lysosomal acid lipase phenocopied severe steatohepatitis, rescued by FXR agonism-mediated reactive oxygen species suppression. The presented key methodology and preliminary results offer a new approach for studying a personalized basis for inflammation and fibrosis in humans, thus facilitating the discovery of effective treatments.

DOI: https://doi.org/10.1016/j.cmet.2019.05.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30247-5