Stem Cell R&D - 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 (Jensen et al 2009). 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 maintained in culture in multi-well formats. The cells exhibit specific markers and functional properties similar to their adult counterparts (Söderdahl et al, 2007, Brolén et al 2010). For example, alpha-1-antitrypsin, liver-fatty-acid-binding-protein, albumin and cytokeratin 8 and 18 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. Cyp1A-, Cyp 2C-, Cyp3A- and GSTα-activity), and glycogen storage. Furthermore, several transporters are expressed such as MRP2, BSEP and OCT-1. Cells are delivered fresh, ready-to-use, in 24- or 96-well format both within Europe and to the rest of the world.

APPLICATIONS

The hepatocyte-like cells can efficiently be used for various in vitro applications such as in basic hepatic research and in drug discovery. The cells are currently tested in several specific applications, e.g. target evaluation, different toxicity assays and viral infection. Data from those studies will be available within short.

Hepatocyte-like cells are also generated from human iPS cells, and this product will be available in the near future.

REFERENCES

Brolén G et al, Hepatocyte-like cells derived from human embryonic stem cells specifically via definitive endoderm and a progenitor stage, J Biotechnology. 2010, 145:284-294.

Mantel N et al, Potential markers of attenuation of YF virus after infection of stem cell-derived human hepatocytes with wild-type Asibi or live-attenuated YF 17D virus, Supplement to the American Journal of tropical Medicine and Hygiene.
Volume 83, November 2010, Number 5, abstract 12.

Jensen, J et al, Human embryonic stem cell technologies and drug discovery J Cell Physiol.
2009 Jun;219(3):513-9.

Synnergren et al DOI:10.1089/scd.2009.0220, Stem Cells & Development, 2009.

Söderdahl et al. Toxicology In Vitro. 2007 Aug;21(5):929-37.

Ek et al. Biochemical Pharmacology 2007 Aug 1;74(3):496-503.