马克斯·普朗克分子细胞生物学和遗传学研究所Meritxell Huch小组揭示了小鼠肝集合体模型门静脉周围结构和胆道纤维化。相关论文于2025年5月29日发表在《自然》杂志上。

该研究组描述了一个由成人肝细胞、胆管细胞和间充质细胞组成的多细胞类器官系统，它概括了肝脏门静脉周围区域的结构，当被操纵时，可以模拟胆汁淤积损伤和胆道纤维化的各个方面。研究人员首先产生了具有功能性胆管网络的可再生肝细胞类器官，保留了体内组织的形态特征。通过将这些细胞与胆管细胞和门静脉成纤维细胞结合，该团队产生了模拟门静脉周围区域细胞相互作用的组装体。集合体是功能性的，持续地将胆汁从胆管排入胆管。

引人注目的是，操纵门脉间充质细胞的相对数量足以诱导纤维化样状态，而不依赖于免疫室。通过产生突变型和野生型细胞的嵌合组合体，或基因敲除后，该研究团队证明了他们的系统可以用于研究基因功能和细胞自主机制。综上所述，该课题组研究人员在一个一体化的模型中证明，肝组装体是一个适合研究胆管形成、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道纤维化的体外系统。

据悉，肝脏疾病建模需要能够复制疾病进展的体外系统。目前的组织衍生类器官无法复制体内观察到的复杂细胞组成和组织结构。

附：英文原文

Title: Mouse liver assembloids model periportal architecture and biliary fibrosis

Author: Dowbaj, Anna M., Sljukic, Aleksandra, Niksic, Armin, Landerer, Cedric, Delpierre, Julien, Yang, Haochen, Lahree, Aparajita, Khn, Ariane C., Beers, David, Byrne, Helen M., Seifert, Sarah, Harrington, Heather A., Zerial, Marino, Huch, Meritxell

Issue&Volume: 2025-05-29

Abstract: Modelling liver disease requires in vitro systems that replicate disease progression1,2. Current tissue-derived organoids fail to reproduce the complex cellular composition and tissue architecture observed in vivo3. 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 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. Strikingly, 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. Taken 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.

DOI: 10.1038/s41586-025-09183-9

Source: https://www.nature.com/articles/s41586-025-09183-9