Three is Better Than One: Three-Organoid System Opens Door for More Comprehensive Study and Treatment of Liver Diseases

The Context: Organoids (3D aggregates of human tissue made from stem cells) are advantageous for studying disease and development since they recapitulate the way different cell types interact within the body. However, most current organoid studies only model one organ, and many diseases, such as liver disease, affect multiple tissue types.

The Study: A new system containing 3 organoids (modeling the liver, pancreas, and bile duct) is giving a more comprehensive picture of how these tissues interact in liver development and disease. The study, which appears in Nature, is led by NYSCF – Robertson Stem Cell Investigator, Cincinnati Children’s Hospital Assistant Professor of Pediatrics, and Yokohama City University Associate Professor of Regenerative Medicine Dr. Takanori Takebe.

The Importance: The 3-organoid system provides a more accurate depiction of cell behavior in liver disease and will facilitate patient-specific study, diagnosis, and treatment of liver disease.

Organoids are revolutionizing biomedical research. These 3-dimensional aggregates of human tissue made from stem cells provide a more comprehensive picture of what happens in the human body by showing how different cell types behave and interact in development and disease. Thanks to a new study in Nature from NYSCF – Robertson Stem Cell Investigator, Cincinnati Children’s Hospital Assistant Professor of Pediatrics, and Yokohama City University Associate Professor of Regenerative Medicine Takanori Takebe, MD, organoids models are getting even more detailed by including tissues from multiple organs.

When it Comes to Organoids, the More the Merrier

Dr. Takebe’s study is groundbreaking because it models not just one type of tissue, but three. By combining organoids made from cells of the human liver, pancreas, and bile duct, this system provides a more complete depiction of how a group of related tissues interact.

“The connectivity is the most important part of this,” said Dr. Takebe in a press release from Cincinnati Children’s Hospital. “What we have done is design a method for producing pre-organ formation stage tissues so that they can develop naturally. We are maximizing our capacity to make multiple organs much like our body does.”

Growing a Model Digestive Tract

To make the organoids, Dr. Takebe’s team began with stem cells. They experimentally guided the stem cells into becoming ‘spheroids’ (miniature, spherical aggregates of tissue) made of cells found in the foregut and midgut.

The team then suspended the spheroids next to each other in a dish filled with a special gel which helps cells grow. The cells from the different spheroids then began to interact—sparking themselves, and each other, to mature into more specialized cells.

Click here for an illustrative video of the study.

Over the next 70 days, the cells continued to branch out, forming groups of cells specific to certain organs. Surprisingly, the organoids even started processing bile acids, a hallmark of digestion.

“This was completely unexpected. We thought we would need to add ingredients or other factors to push this process,” remarked Hiroyuki Koike, PhD, the study’s lead author. “Not trying to control this biological process led us to this success.”

Implications for Disease Research and Treatment

Dr. Takebe, who originally wanted to be a transplant surgeon, turned his attention to organ generation when he learned about the shortages of donor organs available to patients. This study is an important step toward liver generation, but to grow a liver from stem cells that is large and functional enough for transplantation will require much more research. As a next step, Dr. Takebe is focusing on adding immune cells and blood vessel precursors to his organoids.

In the more immediate future, the organoid system could serve as an important tool for research, diagnosis, and drug testing.

The organoids carry the genetic information of the person from which they are derived, allowing for better understanding of how our genes influence our organ development, both in healthy individuals and in those with liver disease. Knowing more about what goes wrong in early stages of liver disease will help scientists develop new treatments. Additionally, testing drugs on the organoids will help researchers determine which therapies will work best for which patients.

“Current liver regenerative medicine approaches suffer from the absence of bile duct connectivity,” Takebe says. “While much work remains before we can begin human clinical trials, our multi-organoid transplant system is poised to solve this issue and may someday provide a life-long cure for patients with liver diseases.”

Journal Article:

Modelling human hepato-biliary-pancreatic organogenesis from the foregut–midgut boundary
Hiroyuki Koike, Kentaro Iwasawa, Rie Ouchi, Mari Maezawa, Kirsten Giesbrecht, Norikazu Saiki, Autumn Ferguson, Masaki Kimura, Wendy L. Thompson, James M. Wells, Aaron M. Zorn & Takanori Takebe. Nature. 2019. https://www.nature.com/articles/s41586-019-1598-0

Image credit: Cincinnati Children’s Hospital Medical Center