Dowbaj Anna M, Sljukic Aleksandra, Niksic Armin, Landerer Cedric, Delpierre Julien, Yang Haochen, Lahree Aparajita, Kühn Ariane C, Beers David, Byrne Helen M, Seifert Sarah, Harrington Heather A, Zerial Marino, Huch Meritxell
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Center for Organoid Systems, Technische Universität München, Munich, Germany.
Nature. 2025 May 29. doi: 10.1038/s41586-025-09183-9.
Modelling liver disease in vitro requires systems that replicate disease progression. Current tissue-derived organoids do not reproduce the complex cellular composition and tissue architecture observed in vivo. Here, we describe a multicellular organoid system composed of adult hepatocytes, cholangiocytes and mesenchymal cells that recapitulates the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids with a functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that mimic the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Of note, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or after gene knockdown, we show proof of concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Together, we demonstrate that liver assembloids represent a suitable in vitro system to study bile canaliculi formation, bile drainage and how different cell types contribute to cholestatic disease and biliary fibrosis in an all-in-one model.
在体外模拟肝脏疾病需要能够复制疾病进展的系统。目前源自组织的类器官无法重现体内观察到的复杂细胞组成和组织结构。在此，我们描述了一种由成人肝细胞、胆管细胞和间充质细胞组成的多细胞类器官系统，该系统概括了肝门周区域的结构，并且在经过操控后能够模拟胆汁淤积性损伤和胆管纤维化的各个方面。我们首先生成了具有功能性胆小管网络的可重复性肝细胞类器官，这些类器官保留了体内组织的形态特征。通过将这些肝细胞类器官与胆管细胞和门周成纤维细胞相结合，我们生成了模拟肝门周区域细胞相互作用的组装体。组装体具有功能，能够持续地将胆小管中的胆汁引流到胆管中。值得注意的是，操控门周间充质细胞的相对数量足以诱导出类似纤维化的状态，而无需免疫细胞参与。通过生成突变型和野生型细胞的嵌合组装体，或在基因敲低后，我们证明了我们的系统适用于研究基因功能和细胞自主机制这一概念。总之，我们证明了肝脏组装体是一种合适的体外系统，可用于在一体化模型中研究胆小管形成、胆汁引流以及不同细胞类型如何导致胆汁淤积性疾病和胆管纤维化。
