Scientists in Japan have grown functioning human liver tissue from stem cells. They say their work shows it may be possible to harness the technology to alleviate the acute shortage of donor tissue for transplants.
In a 3 July online issue of Nature, Takanori Takebe of the Yokohama City University (YCU) Graduate School of Medicine and colleagues, write:
“To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells.”
To achieve the feat, the team first grew tiny “liver buds” from a type of human stem cells (hiPSCs) in a culture, then transplanted them into live mice. The cells produced functional human liver tissue, complete with blood vessels.
Although efforts must now be made to ensure these techniques will work in human patients, the scientists say their study is “proof- of-concept” that “organ-bud transplantation provides a promising new approach to study regenerative medicine”.
Since embryonic stem cells were discovered in 1981, years of work in labs around the world have failed to produce a complex organ such as the liver, complete with blood vessels, from these undifferentiated precursor cells.
There is now a belief that it is essentially impractical to try and replicate in a test tube, the complex interactions that take place among different types of cells and tissues when an organ develops.
However, with their new study, Takebe and colleagues challenge this notion, and say you can overcome this barrier if you focus on the earliest process of organ generation, namely the cellular interactions that occur during “organ bud” development.
During the early stages of liver formation, three-dimensional liver buds, complete with blood vessels, form from the tissue of the foregut. A key element in this process is the orchestration of signals among three types of stem cell: liver, mesenchymal and endothelial.
Observing this process led Takebe and colleagues to wonder if they could mimic the three-dimensional (3D) liver bud formation by mixing these three cell types together in a two-dimensional (2D) petri dish.
So they took human induced pluripotent stem cells (hiPSCs) and mixed them with human endothelial cells and human mesenchymal cells and cultured them in a petri dish.
They were astonished to find that even though they cultured the cells in 2D, they organized themselves into 3D liver buds.
Tests (immunostaining and gene expression analyses) revealed a striking resemblance between the buds grown in the dish and liver buds that grow naturally in tissue.
When the team transplanted the liver buds grown from hiPSCs in the petri dish into live mice, within 48 hours the buds were already developing a blood supply by growing “functional vasculatures” linked to nearby blood vessels.
The formation of a viable blood supply also triggered liver functions resembling those observed in adult liver tissue, such as protein production and the ability to metabolize certain drugs.
Plus, when transplanted into mice with liver failure the, buds restored liver function.
Although the results now need to be confirmed in other labs, it looks like the initial enthusiasm fired by the discovery of stem cells, that went into a lull when the practical barriers were discovered, may be rekindled.
The team says in a statement: “These results highlight the enormous therapeutic potential [of] using in vitro grown organ bud transplantation for treating organ failure.”
Apart from the huge difference such an approach might make in addressing the shortage of organs for transplant, there are other areas of potential application for the methods developed in this study.
For example, they could be very useful in drug development. The liver is a big clean-up organ, and a lot of compounds are broken down there to prevent them poisoning the body. This makes the liver a prime target for toxicity caused by drugs.
So an important part of drug development is testing their effect on the liver. Currently these tests use cells harvested from livers taken from dead donors, or produced by cell lines in the lab, or stem cells derived from donated livers, or animals.
But each of these testing models has limitations. They don’t perform in exactly the same way as livers in live patients, and they can be expensive and time-consuming to prepare.
Takebe and colleagues say the methods they have used in this study open up a new way to grow fully functioning liver cells from hiPSCs that could then be used to test toxicity of new drugs.
Funds from the Japan Science and Technology Agency, and the Ministry of Education, Culture, Sports, Science and Technology of Japan, helped finance the study.
Written by Catharine Paddock PhD