A three-dimensional liver model under development may in the future be used to test the safety of pharmaceuticals and to develop personalised treatments for liver diseases. Led by University Researcher Yan-Ru Lou, the high-risk research project funded by the Academy of Finland aims to generate even better functional, three-dimensional liver organoids, or cell cultures, from human stem cells. These pluripotent stem cells can differentiate into the cell type of any kind of tissue. The objective is to generate a 3D liver cell model equivalent to the operation of the human liver.
“Drug-induced liver injury is one of the most common types of damage caused by pharmaceuticals. Up to one third of pharmaceuticals are taken off the market due to drug-induced liver injury. Toxic pharmaceuticals should be detected already during their development. This would save money and increase the safety of the pharmaceuticals entering the market,” says Lou, who has also worked on the EU-funded LIV-ES project, whose objective was to generate liver cells from embryonic human stem cells.
Research into the hepatic differentiation of human pluripotent stem cells has been going on for over ten years, but the differentiation of the cells in the research has primarily been directed using soluble growth factors. According to Lou, they play an important role in cell differentiation in both our bodies and in artificial laboratory conditions, but at the same time, the natural extracellular matrix environment of hepatocytes, the primary liver cell type, has been neglected.
“In our research, we aim to imitate as closely as possible the kind of environment the tissue would really have. With the exception of blood cells, all other cells in our body are always in a specific extracellular matrix. In the research, we use the main structural components of the extracellular matrix naturally present in the liver, and biomaterials imitating those components, so that the growth environment of the cells would be as natural as possible even in a laboratory,” says Lou.
Personalised treatment for liver diseases
Pharmaceutical development is slow and expensive, so means for making it faster are welcome. The liver model developed by Lou’s team would have several potential applications in pharmaceutical development. Firstly, it could be used to test the toxicity of new pharmaceuticals.
“It’s important during pharmaceutical development to obtain reliable and predictive data of new drugs under development. Cell models of human origin can provide better data than animal testing, because drugs are eliminated by different means in, for example, human and rat livers. This model could therefore be used to obtain more reliable data on unknown drugs, while reducing the amount of animal testing by the pharmaceutical industry.”
The liver model could also be used to develop a disease model to test the effect of new drugs on the liver. In other words, the model would be modified into a “sick” version, enabling the testing of which drugs can be used to cure a specific disease. Lou also mentions the personalised liver model that could be built from the patient’s own cells, or made to match their genome.
“All people react differently to drugs, so the personalised liver model could allow us to screen the suitable treatment for each patient. Our research could also benefit the building of a functional transplant liver. A liver transplant is the only form of treatment for many people suffering from liver diseases. Chronic liver diseases affect more than 600 million people around the world.”
The liver has an extremely complex structure, and its differentiation process has a large number of stages.
“The final application of the cell culture plays a central role in the development of the liver models. The Medicines Decree has a say on when the model can be used in the industry. The model must not be too complex or too expensive,” Lou says.
Venture capital may enable breakthroughs
“We know that the extracellular matrices influence the differentiation of liver cells, but we don’t yet know their specific role. No one has previously created a liver model using 3D-grown pluripotential stem cells. Researching a new and uncharted subject is really challenging, fascinating and exciting,” says Lou.
Lou also has other ongoing research projects supporting this research. Data from one piece of research may help the progress of another research project. Backup plans are another means of Lou for managing the risks of the research.
“The impact of high-risk research is high, when it succeeds. From society’s perspective, this kind of research is important if we wish to improve in the field of research and make breakthroughs in science”.
Finnish text by Anna-Riikka Oravakangas
Photo by Anita Westerback
- Academy of Finland supports scientific risk-taking with purpose-made funding (Academy press release, 2 Sep 2015)