Blueprint for stemm cell differentitaion into liver cells (hepatocytes)

Stem cell research gets more and more important because these cells can be directed to differentiate into practically all mature cell types. This represents a potential solution for therapeutics of severely damaged organs and also an alternative to animal drug and toxicity testing. Nonetheless an essential question still remains: How similar are differentiated stem cells to the desired mature cells, e.g. liver cells? Scientists at IfADo – Leibniz Research Centre for Working Environment and Human Factors in cooperation with partners from EU and UK developed a method for precisely assessing the degree of stem cell-differentiation into mature liver cells (i.e. hepatocytes) based on whole-genome gene expression analysis and statistical models.

Left: liver cells (hepatocytes), right: hepatocyte-like cells. Differences are almost invisible to the naked eye. A new mathematical approach based on gene expression profiles shows how big the similarity really is. © IfADo / University of Edinburgh
Left: liver cells (hepatocytes), right: hepatocyte-like cells. Differences are almost invisible to the naked eye. A new mathematical approach based on gene expression profiles shows how big the similarity really is. © IfADo / University of Edinburgh

The liver has the spectacular ability to regenerate. However, this capacity is compromised after severe acute damage or in chronic disease such as cirrhosis. In these situations, the only solution up to now is organ transplantation which comes often too late and implies high risks for the patients. Luckily, scientists around the world are working on a promising alternative: stem cell therapy. Stem cells have the capacity to change (i.e. differentiate) into every cell of the human body – skin, nerve or even liver cells, so called hepatocytes. However, the degree of similarity between stem cell-derived tissue cells (for example, hepatocyte-like cells) and primary hepatocytes it is still controversial. This is a very important issue, because the application of these cells for therapeutic or toxicity testing requires that they perform all functions of a mature tissue.

Scientists at in cooperation with partners from EU and UK developed a method for comparing hepatocyte-like cells and original (primary) human hepatocytes based on their gene expression profiles. Given the huge number of genes (apx. 22.000) in the human genome, this comparison is not an easy task. The scientists clustered the thousands of genes according to special functions and regulatory principles by applying mathematical models. For example, some genes are responsible for the expression of proteins involved in metabolism, while others regulate cell proliferation. Particularly relevant for hepatocytes are Cytochromes (P450) and Sulfotransferases because they decompose poisonous substances – a main task of the liver. Genes regulating cell cycle are on the other hand less relevant because hepatocytes do not proliferate at a high rate in a healthy liver.

The scientists applied the mathematical models to compare these gene clusters using real liver cells (primary human hepatocytes), stem cells and six different stem cell-derived hepatocyte-like cells. The comparison shows that in some gene clusters hepatocyte-like cells are very similar to original hepatocytes, including many genes involved in drug and xenobiotic metabolism. Surprisingly, other gene clusters in HLC indicated that these cells acquire properties of additional tissues, including colon and fibroblasts. Importantly, the analysis revealed the mechanisms responsible for the expression of genes associated with each tissue type. This approach allows the scientist to precisely determine the extent of differentiation of from stem cells, the degree of acquisition of liver features and the appearance of undesired additional tissue types.

The scientists made an important step towards stem cell therapy for liver damage. Furthermore, since cultivated liver cells are a basic tool for testing the effects of new medicinal drugs, hepatocyte-like cells can become an important alternative to animal testing. The results are also important because medicinal and toxic substances are currently being tested with hepatocyte-like cells, and now the scientists can know how trustworthy those results can be.

This is the first time that such a systematic comparison has been performed. The recent published study in the Journal of Hepatology offers a blueprint for research in stem cell differentiation of liver cells. Dr. Patricio Godoy, head of the junior group „Liver Toxicology“ at the , is the coordinator of the international project.

Original publication:
Godoy, P., Schmidt-Heck, W., Natarajan, K., Lucendo-Villarin, B., Szkolnicka, D., Asplund, A., Bjorquist, P., Widera, A., Stoeber, R., Campos, G., Hammad, S., Sachinidis, A., Damm, G., Weiss, T.S., Nussler, A., Synnergren, J., Edlund, K., Küppers-Munther, B., Hay, D., Hengstler, J.G., Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells, Journal of Hepatology (2015), doi: http://dx.doi.org/10.1016/j.jhep.2015.05.013

Contact:
Dr. Patricio Godoy
Head of the junior group: Liver Toxicology
Phone: +49 / 231 1084 256