Placenta-Derived Signals Improve Liver Organoid Size and Function

Organoids—miniature, lab-grown structures designed to mimic human organs—have become powerful tools in medical research and regenerative medicine. Yet despite their potential, their development and functionality often fall short of clinical needs. A new study from The University of Tokyo offers a promising strategy to overcome this hurdle, using a placenta-derived protein to dramatically enhance liver organoid growth.

Published in Nature Communications, the research reveals that IL1α, a protein found in the placenta, can significantly promote the expansion of liver organoids derived from human induced pluripotent stem cells (hiPSCs)—but only under carefully controlled low-oxygen (hypoxic) conditions.

Led by Dr. Yoshiki Kuse and Professor Hideki Taniguchi at The Institute of Medical Science, the research team aimed to tackle one of the biggest challenges in organoid development: achieving organoids that are large and functional enough to be useful for disease modeling and future therapeutic applications. Current organoid systems often struggle to replicate the complex signaling environments needed for proper tissue development.

To address this, the researchers looked to early fetal development for inspiration. During pregnancy, the placenta plays a central role in supplying oxygen and proteins critical to organ formation. However, the specific interactions between placental factors and developing tissues—especially those that drive liver progenitor cell growth—remain poorly understood.

Focusing on a key developmental window in mouse embryos (embryonic days 10–11), the researchers observed that liver development occurs in an environment marked by localized blood perfusion and hypoxia. During this time, the placenta secretes several growth factors, including IL1α, which appeared to play a central role.

The team isolated IL1α and introduced it into cultures of hiPSC-derived liver organoids under hypoxic conditions. They then transitioned to a regulated oxygen supply to simulate natural developmental processes. The results were striking: organoids treated with IL1α grew up to five times larger than controls and produced significantly higher levels of liver-specific proteins, indicating enhanced functionality.

“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,” said Dr. Kuse.

Further investigation using single-cell RNA sequencing revealed that IL1α triggers hepatoblast proliferation through the SAA1-TLR2-CCL20-CCR6 signaling pathway. This finding not only deepens our understanding of how external cues shape organ development but also highlights a novel method for boosting organoid growth.

The implications of this discovery could be far-reaching. By integrating placenta-derived factors into organoid culture systems, researchers could develop more accurate disease models and advance efforts toward lab-grown organs for transplantation.

Importantly, the team believes this method could be adapted for other organoid types, opening the door to broader applications in personalized medicine and regenerative therapies.

While acknowledging that their current setup doesn’t fully replicate the dynamic environment of a developing fetal liver, the researchers see their work as a key step forward. They propose future studies should explore perfusion-based culture systems that can continuously deliver oxygen and placental proteins, better mimicking physiological conditions.

“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,” Dr. Kuse added.

Altogether, this research enhances our understanding of liver development and offers a compelling new approach to scaling and refining organoid models, grounded in the biology of early human growth.