Organoids—tiny, lab-grown replicas of human organs—have long-held promise for modeling diseases and testing therapies. But there's a catch: making them large and functional enough to mirror real human tissue remains a stubborn challenge. The key to overcoming this obstacle may lie not in synthetic tweaks but in nature itself—specifically, the womb.

In a groundbreaking study published March 13, 2025, in Nature Communications, researchers from The Institute of Medical Science at The University of Tokyo have discovered how placental factors can dramatically enhance the growth of liver organoids derived from human induced pluripotent stem cells (hiPSCs). Led by Dr. Yoshiki Kuse and Professor Hideki Taniguchi, the team zeroed in on the placenta’s role during fetal development, uncovering a specific growth factor that jumpstarts organoid proliferation.

From Mouse Embryos to Mega Organoids

The scientists began by examining liver development in mouse embryos between embryonic days 10 and 11, a critical window when blood flow increases and oxygen levels drop—a state known as hypoxia. During this stage, the placenta floods the embryo with a cocktail of growth-promoting proteins. Among them, one protein stood out: IL1α.

The team isolated IL1α and introduced it to liver organoids grown from hiPSCs, replicating the hypoxic conditions found in the womb. Once the organoids were stabilized, they were gradually exposed to oxygen, mimicking natural developmental transitions. The result? Liver organoids that were up to five times larger than untreated controls—and, crucially, more functional, producing higher levels of liver-specific proteins.

“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,” explains Dr. Kuse.

Mapping the Growth Pathway

Digging deeper, the team used single-cell RNA sequencing to trace how IL1α triggers this growth. They discovered that the protein activates a molecular cascade—SAA1-TLR2-CCL20-CCR6—that stimulates the expansion of hepatoblasts, the progenitor cells that form liver tissue. This finding doesn’t just explain how liver growth is regulated during development; it also gives researchers a new playbook for engineering better organoids.

This new knowledge is more than academic. By fine-tuning how placenta-derived factors are delivered, scientists could develop more complex, physiologically relevant organ models. And while liver organoids were the focus of this study, the implications are far broader. “This approach might be applicable to developing other types of organoids as well,” the researchers suggest.

Toward Functional, Transplant-Ready Organs

There are still hurdles to overcome. The current method, while highly effective, doesn’t fully recreate the complex, dynamic environment of a developing fetus. The team’s next move? Creating perfusion-based culture systems that can continuously deliver growth factors and oxygen—taking one more step toward bioengineered organs that could eventually replace damaged human tissues.

“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,” says Dr. Kuse.

This study shines a spotlight on the power of developmental biology to guide innovation in regenerative medicine. By tapping into nature’s own blueprint for organ formation, scientists are getting closer to building lab-grown organs that don’t just look like the real thing—they work like it, too.