Project launch: HyCell
The “HyCell” project, led by Dr. Patrick Nell from the Toxicology Department of the Leibniz research centre for Working Environment in Dortmund (IfADo), just started. The research project is dedicated to the correction of stemm cell-derived hepatocyte hybrid cells for better investigation of liver diseases. The project is being funded by the DFG for three years.
To this day, research into the origin, development and therapy of liver diseases and the prevention of DILI (drug induced liver injury) depends on animal models and cell-based in vitro model systems. However, both animal and vitro models face limitations in their applicability and representation of primary human hepatocytes (PHH) in vivo (liver cells in the human body). Animal models lack throughput capacity, do not reflect important species differences, are costly and ethically controversial. In vitro systems, on the other hand, do not adequately reflect the two phases of metabolism, catabolism and anabolism, among others, even when using limited liver cells isolated from human tissue, which is the current gold standard.
Pluripotent stem cells as an alternative
Pluripotent stem cells are responsible for the formation of all tissues and organs, including their various cell types during later development. Since their discovery, findings from developmental biology studies have been used to derive protocols that allow mimicking certain processes of development and cell differentiation in vitro to derive specialized cell types from pluripotent stem cells. Based on this technology, the generation of stem cell-derived hepatocyte-like cells (HLC) offers a perspective of unlimited availability of donor-specific cell material that could replace primary human hepatocytes as the gold standard for studying hepatotoxicity in vitro.
Challenges and aim of the project
However, challenges remain that prevent the implementation of HLC, especially in regulatory toxicology. On the one hand, HLC have a lower expression of liver-associated genes compared to PHH. Secondly, the expression of “unwanted genes”, for example those normally required by other cell types of the gastrointestinal tract, leads to a hybrid cell identity. This combination of immature liver-specific properties and hybrid cell identity must be overcome in order to establish liver cells generated from stem cells as a reliable in vitro system and alternative to animal experiments.
The aim of the project therefore is to limit hybrid differentiation by targeted manipulation of the affected gene regulatory networks and improve the performance and reliability of stem cell-derived hepatocytes for use in drug and toxicity testing and development of future cell therapies for liver diseases. This phenotypic optimization of HLC aims to address key challenges of current in vitro testing platforms, including the low availability of primary donor material for in vitro testing with human cells, high cost, ethical considerations, lack of accuracy, and limited throughput of animal testing.