Human embryonic stem cell technologies and drug discovery

Abstract

Development of new drugs is costly and takes huge resources into consideration. The big pharmaceutical companies are currently facing increasing developmental costs and a lower success-rate of bringing new compounds to the market. Therefore, it is now of outmost importance that the drug-hunting companies minimize late attritions due to sub-optimal pharmacokinetic properties or unexpected toxicity when entering the clinical programs. To achieve this, a strong need to test new candidate drugs in assays of high human relevance in vitro as early as possible has been identified. The traditionally used cell systems are however remarkably limited in this sense, and new improved technologies are of greatest importance. The human embryonic stem cells (hESC) is one of the most powerful cell types known. They have not only the possibility to divide indefinitely; these cells can also differentiate into all mature cell types of the human body. This makes them potentially very valuable for pharmaceutical development, spanning from use as tools in early target studies, DMPK or safety assessment, as screening models to find new chemical entities modulating adult stem cell fate, or as the direct use in cell therapies. This review illustrates the use of hESC in the drug discovery process, today, as well as in a future perspective. This will specifically be exemplified with the most important cell type for pharmaceutical development-the hepatocyte. We discuss how hESC-derived hepatocyte-like cells could improve this process, and how these cells should be cultured if optimized functionality and usefulness should be achieved.

Scale‐up of cell culture bioreactors using biomechatronic design

“…This may be of particular value for new emerging technology such as stem cell manufacturing, where the cellular transformation process is quite different from traditional bioprocesses, and where scale-up principles are at present not founded [6,39].…”

“…Increasing industrial use of mammalian cell cultures for a variety of purposes, such as production of biopharmaceuticals [3][4][5] and expansion and differentiation of embryonic stems [6][7][8][9], emphasizes the need of reliable and successful scale-up methodology.…”

Actions of endocrine-disrupting chemicals on stem/progenitor cells during development and disease

“…Therefore, they have been considered as a source of various cell types for organ regeneration or tissue replacement after injury or disease (Odorico et al 2001). It has also been postulated that hES cells could be used for reproductive toxicity screening in vitro (Krtolica & Giritharan 2010) as well as for drug discovery to minimize unexpected toxicity when entering a clinical trial (Jensen et al 2009). Using undifferentiated hES cells in an in vitro screening assay, Kim et al (2006) reported that exposure to the organic compounds such as nonylphenol (NP) and octylphenol (OP) decreased expression of Oct4 and Nanog in a dose-dependent manner.…”

Concise Review: Human Pluripotent Stem Cell-Based Models for Cardiac and Hepatic Toxicity Assessment

“…Thus, many scientists working on optimization of functions of hepatic cell cultures, and applicability of such cells in safety studies, are exploring the use of three-dimensional (3D) cell systems. This includes seeding matrix-like scaffolds in multiwell formats or using more advanced and organ-like setups like various bioreactors [28]. Moreover, the use of different liver cell types such as endothelial cells, Kuppfer cells, or Stellate cells in combination with hepatocytes in these models may increase assay predictability.…”