iPS細胞からヒト肝臓の類洞血管を再構築～凝固因子分泌能を高めたオルガノイドの創出により、血友病の出血症状を改善～

2025-06-26 東京科学大学

図1. 凝固等の機能が強化された、臓器特異的欠陥構造をを有する肝臓オルガノイドを創出
A.本研究で得られた肝臓オルガノイドの創出技術と、類洞内皮細胞が関与する機能の概略。 B. 肝臓オルガノイドを構成する、ASGR1陽性肝細胞(赤)、CD32B陽性類洞内皮細胞(緑)、および細胞核(青)を染色した3次元立体構造の蛍光画像。 C. 肝臓オルガノイドの培養液中に分泌された凝固第VIII因子(FVIII)の量。

<関連情報>

• https://www.isct.ac.jp/ja/news/b0s0r6osdalz
• https://www.isct.ac.jp/plugins/cms/component_download_file.php?type=2&pageId=&contentsId=1&contentsDataId=1816&prevId=&key=1ce18e78a847ab169d3d2ac1ec7ad6b7.pdf
• https://www.nature.com/articles/s41551-025-01416-6

多能性幹細胞由来ヒト肝芽オルガノイドにおける洞様血管の自己組織化 Self-organization of sinusoidal vessels in pluripotent stem cell-derived human liver bud organoids

Norikazu Saiki,Yasunori Nio,Yosuke Yoneyama,Shuntaro Kawamura,Kentaro Iwasawa,Eri Kawakami,Kohei Araki,Junko Fukumura,Tsuyoshi Sakairi,Tamaki Kono,Rio Ohmura,Masaru Koido,Masaaki Funata,Wendy L. Thompson,Pamela Cruz-Encarnacion,Ya-Wen Chen & Takanori Takebe
Nature Biomedical Engineering  Published:25 June 2025
DOI:https://doi.org/10.1038/s41551-025-01416-6

Abstract

The induction of tissue-specific vessels in in vitro living tissue systems remains challenging. Here, we directly differentiated human pluripotent stem cells into CD32b⁺ putative liver sinusoidal progenitors by dictating developmental pathways. By devising an inverted multilayered air–liquid interface culture, hepatic endoderm, septum mesenchyme, arterial and sinusoidal quadruple progenitors self-organize to generate and sustain hepatocyte-like cells neighboured by divergent endothelial subsets composed of CD32b^lowCD31^high, LYVE1⁺STAB1⁺CD32b^highCD31^lowTHBD^–vWF^– and LYVE1^–THBD⁺vWF⁺ cells. WNT2 mediates sinusoidal-to-hepatic intercellular crosstalk potentiating hepatocyte differentiation and branched endothelial network formation. Intravital imaging reveals the iPS-cell-derived putative liver sinusoidal endothelial progenitor develops fully perfused human vessels with functional sinusoid-like features. Organoid-derived hepatocyte- and sinusoid-derived coagulation factors enable correction of in vitro clotting time with Factor V-, VIII-, IX- and XI-deficient plasma, and rescues the severe bleeding phenotype in haemophilia A mice on transplantation. Advanced organoid vascularization technology allows for interrogating key insights governing organ-specific vessel development, paving the way for coagulation disorder therapeutics.