Stem cells in toxicity testing

Abstract

Recently, stem cells have attracted much interest as tools for toxicity testing (Heng et al. 2009; Snykers et al. 2007; Aurich et al. 2007; Ruhnke et al. 2005). Therefore, the editors are pleased that Prof. Anna Wobus from the Leibniz Institute in Gatersleben and Dr. Peter Loser from the Robert-Koch-Institute in Berlin have contributed a comprehensive review about the present state and future perspectives of stem cells in toxicology research to this issue of our journal (Wobus and Loser 2011; this issue). Principally, two approaches have been used in this Weld of research. Stem cells in culture are stimulated to undergo a certain developmental process, for example to recapitulate a certain phase of embryonic development. Then by addition of test compounds, it can be analyzed whether the developmental process is compromised. This strategy has been successfully applied to identify a number of teratogens (Eckardt and Stahlmann 2010). A large EU-consortium, ESNATS, currently uses this approach to establish assays for developmental neurotoxicity. For this purpose, human embryonic stem cells are stimulated to undergo early stages of neurodiVerentiation. A second approach aims at generating mature cells, such as hepatocytes, cardiomyocytes or neurons, which could then be used as target cells for “adult” toxicity testing. In principle, this approach is attractive as it could lead to an unlimited supply of primary human cells. A few years ago, there was a hype regarding studies claiming that they could generate functional hepatocytes from stem cells (review: Hengstler et al. 2005). For example, Schwartz et al. reported that progenitor cells from bone marrow diVerentiate into “functional hepatocyte-like cells” (Schwartz et al. 2002), while Jang et al. claimed that “hematopoietic stem cells convert into liver cells within days without fusion” (Jang et al. 2004). However, it has become clear that these were overoptimistic interpretations (Hengstler et al. 2005; Brulport et al. 2007; Hewitt et al. 2007). Direct comparison of the latter stem cell–derived “hepatocyte-like cells” with primary hepatocytes has shown that huge diVerences remain; therefore, replacement of primary by stem cell–derived hepatocytes is not yet possible. Today, primary hepatocytes are still the most reliable and most frequently used in vitro tool for studies of drug metabolism, enzyme induction and hepatotoxicity (Hewitt et al. 2007; Schumann et al. 2009; Hengstler et al. 2009; Schug et al. 2008; Godoy et al. 2009; Kafert-Kasting et al. 2006; Ruhnke et al. 2005; Ringel et al. 2005; Wang et al. 2009; Ostrowska et al. 2009). Whereas it remains a long way until stem cell–derived hepatocytes can be used for routine applications in Toxicology. The current state of the art article of Anna Wobus and Peter Loser is a must-read for everybody interested in stem cell applications in Pharmacology and Toxicology.