Hepatocytes

Human ES cells have the capacity to differentiate into hepatocyte-like cells and they represent a potential unlimited source for human hepatocytes.

The successful derivation of hepatocytes from hES cells is likely to lead to significant advances in development of various in vitro applications. Investigations of the hepatic risk profile of novel drug candidates at an early stage of development are essential in order to determine any unacceptable safety profile. In particular, liver toxicity and alterations of liver function are the most frequent occurring reasons for toxicology among chemical compounds.

Unexpected human metabolism is today one of the major causes of removal of potential new drugs in drug discovery and development. Moreover, liver metabolism and the interplay between hepatocytes and other organs are important drug targets for metabolic and dyslipidemic diseases. Unfortunately, the complexity and function of the liver is not mirrored by any cell type available for in vitro testing today.

Functional hepatocytes derived from hES cells have the potential to combine a high degree of specific differentiation with an excellent availability for in vitro testing. Novel improved in vitro models based on physiologically relevant human cells will result in more cost-effective assays ultimately leading to lower attrition rates and safer new drugs.

Cellartis AB has established robust protocols that will enable consistent differentiation of hES cells into homogeneous populations of hepatocyte-like cells suitable for use as bio-tools in industrial applications. This, furthermore, opens up new principles for human  hepatotoxicity testing that at the same time lead to a significant decrease in animal experimentation.

The hepatocyte-like cells derived from hES cells, hES-HEP™ 002, are morphologically very similar to adult human hepatocytes grown in vitro and can be efficiently reseeded into multi-well plates and maintained in culture. The cells exhibit specific markers and functional properties similar to their adult counterparts (Söderdahl et al, 2007). For example, alpha-1-antitrypsin, liver-fatty-acid-binding-protein, albumin and several drug transporters are expressed by the cells. These cells also express all important Cytochrome P450 genes (Ek et al. 2007). In addition, many hepatic functions have been detected, such as Phase I and II metabolism (e.g. Cyp1A2, Cyp3A4 and GSTα-activity), and glycogen storage.

The hepatocyte-like cells are currently undergoing further characterisation and optimisation looking at important hepatocyte-specific characteristics, such as other metabolising enzymes, urea synthesis, cell polarity etc. The functionality of these cells is monitored in terms of enzymatic activities and functional responses to treatment with chemical compounds. The hepatocytes derived from hES cells will provide the basis for studies of hepatotoxicity, drug metabolism and hepatic drug targets.

References:

Söderdahl et al. Toxicology In Vitro. 2007 Aug;21(5):929-37.
Ek et al. Biochemical Pharmacology 2007 Aug 1;74(3):496-503.