Mimicking embryonic growth to break barriers in organoid research

Organoids are small-scale models that mimic human organs. These models could help scientists understand diseases and test treatments, and potentially aid in regenerative therapeutic methods. Organoids derived from human induced pluripotent stem cells (hiPSCs), represent a promising frontier in medical research. Unfortunately, growing organoids that are large and functional enough to be truly useful is challenging. Intricate chemical signaling and cellular interactions limit our ability to recreate the processes of tissue development.

In an effort to address these challenges, researchers have been investigating the various factors that contribute to organ growth, particularly in the early stages of fetal development. The placenta plays a vital role in fetal organ growth, supplying essential proteins and oxygen that drive cellular proliferation. Yet, how these elements interact with developing tissues to stimulate the expansion of progenitor cells remains largely unexplored.

In a recent study, a research team led by Dr. Yoshiki Kuse and Prof. Hideki Taniguchi from The Institute of Medical Science, The University of Tokyo, Japan, has now made an important discovery in the field of organoid development. Published online in Nature Communications on March 13, 2025, their paper uncovers how placenta-derived factors can dramatically enhance the growth of liver organoids.

The researchers discovered a crucial biological mechanism by studying mouse embryo development. They found that during a specific stage of liver development (between embryonic days 10 and 11), mouse embryos experience a unique environment characterized by localized blood perfusion and hypoxic (low-oxygen) conditions. Critically, during this stage, the placenta releases various growth factors that play a pivotal role in the development of the liver.

By identifying and isolating these placental factors, the team focused on a specific protein called IL1α. They introduced this factor to hiPSC-derived liver organoids under carefully controlled hypoxic conditions and followed it with controlled oxygenation, mimicking the natural developmental environment. This approach led to remarkable results, as the organoids grew up to five times larger than controls and exhibited improved functional characteristics, including increased production of liver-specific proteins.

Through multiple experiments, the team demonstrated that placenta-derived IL1α significantly enhanced the proliferation of liver progenitor cells called hepatoblasts. “We achieved a prominent growth of hiPSC-derived liver organoids driven by hepatoblast expansion through the careful recapitulation of molecular events governed by extrinsic factors observed in mouse fetal liver,” says Dr. Kuse, explaining their overall strategy.

To explore the underlying mechanisms, the team performed single-cell RNA sequencing analysis, which revealed that IL1α influences hepatoblast expansion through the SAA1-TLR2-CCL20-CCR6 signaling pathway. These insights provide a clearer understanding of how external factors regulate liver development and offer a novel approach to enhancing organoid growth.

These findings could have significant implications in the medical field. By refining techniques to deliver placenta-derived factors in a controlled manner, future research could pave the way for more advanced organoid-based disease models and potentially facilitate the development of lab-grown organs for transplantation. Interestingly, the team suggests that similar approaches might be applicable to developing organoids for other organ types, opening new frontiers in personalized medicine and regenerative therapies.

While the researchers acknowledge that their approach does not yet fully replicate the dynamic in vivo conditions of fetal liver development, their work marks a critical step toward overcoming existing barriers in organoid research. They suggest that future studies should focus on designing perfusion-based culture systems that can continuously supply placenta-derived factors and oxygen, better simulating the physiological conditions of developing organs.

“Our results demonstrate that treatment with the identified placenta-derived factor under hypoxia is a crucial human liver organoid culture technique that efficiently induces progenitor expansion,” concludes Dr. Kuse. Overall, by leveraging insights from developmental biology, this research not only enhances our understanding of liver growth but also highlights new pathways for improving the scalability and functionality of hiPSC-derived organoids.

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Reference                     

DOI: 10.1038/s41467-025-57551-w

Authors: Yoshiki Kuse^1,2, Shinya Matsumoto¹, Syusaku Tsuzuki¹, Erica Carolina^1,3, Takashi Okumura¹, Toshiharu Kasai¹, Soichiro Yamabe^1,3, Kiyoshi Yamaguchi⁴, Yoichi Furukawa⁴, Tomomi Tadokoro⁵, Yasuharu Ueno¹, Takayoshi Oba¹, Naoki Tanimizu¹, and Hideki Taniguchi^1,5

Affiliations:                       

¹Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Japan

²Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Japan

³Graduate School of Frontier Sciences, Computational Biology and Medical Science, Japan

⁴Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Japan

⁵Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Japan

About The Institute of Medical Science, The University of Tokyo
The Institute of Medical Science, The University of Tokyo (IMSUT), established in 1892 as the Institute of Infectious Diseases and renamed IMSUT in 1967, is a leading research institution with a rich history spanning over 127 years. It focuses on exploring biological phenomena and disease principles to develop innovative strategies for disease prevention and treatment. IMSUT fosters a collaborative, interdisciplinary research environment and is known for its work in genomic medicine, regenerative medicine, and advanced medical approaches like gene therapy and AI in healthcare. It operates core research departments and numerous specialized centers, including the Human Genome Center and the Advanced Clinical Research Center, and is recognized as Japan’s only International Joint Usage/Research Center in life sciences.

About Dr. Yoshiki Kuse from The Institute of Medical Science, The University of Tokyo
Yoshiki Kuse is a Visiting Researcher at The Institute of Medical Science at The University of Tokyo and an Assistant Professor at the Faculty of Pharmaceutical Science of Gifu Pharmaceutical University. He obtained his PhD in Pharmaceutical Sciences from Gifu Pharmaceutical University. His research interests include induced pluripotent stem cells, developmental biology, and organoid development. He has published over 40 major papers on these topics.

Funding information:
This work was supported by the Japan Agency for Medical Research and Development AMED; JP13bm0304002, JP20bk0104102h0001, JP21fk0210073s0502, JP23fk0210129s0501, JP23bm1223007, and JP24bk0104174h0001 to Hideki Taniguchi and the Ministry of Education, Culture, Sports, Science, and Technology (MEXT; 21H04830, 24H00641 to Hideki Taniguchi; 19K18034, 22K16440 to Yoshiki Kuse).