肝臓構造を再構築するオールインワンモデル(All-in-one model reconstructs complex liver architecture)

2025-05-29 マックス・プランク研究所

Periportal assembloid, with the three component cell types visualized: cholangiocytes in pink, portal fibroblasts in green, and hepatocyte nuclei in blue; all cell borders are visualized in white.　© Anna M. Dowbaj, Aleksandra Sljukic et al. Nature (2025) / MPI-CBG

<関連情報>

• https://www.mpg.de/24799353/all-in-one-model-reconstructs-complex-liver-architecture
• https://www.nature.com/articles/s41586-025-09183-9

マウス肝アセンブロイドによる大動脈周囲構造と胆道線維症のモデル化 Mouse liver assembloids model periportal architecture and biliary fibrosis

Anna M. Dowbaj,Aleksandra Sljukic,Armin Niksic,Cedric Landerer,Julien Delpierre,Haochen Yang,Aparajita Lahree,Ariane C. Kühn,David Beers,Helen M. Byrne,Sarah Seifert,Heather A. Harrington,Marino Zerial &　Meritxell Huch
Nature  Published:29 May 2025
DOI:https://doi.org/10.1038/s41586-025-09183-9

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract

Modelling liver disease requires in vitro systems that replicate disease progression^1,2. 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.