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To create new in vitro culture models for extrapolating the cell response in vivo, Takezawa et al. have attempted to devise culture substrata of anchorage-dependent cells (Takezawa et al., 1990; Takezawa et al., 1992; Takezawa & Yoshizato, 1997; Takezawa et al., 2000; Takezawa et al., 2002; Takezawa, 2003; Takezawa et al., 2004; Takezawa et al., 2007a; Takezawa et al., 2007b; Takezawa et al., 2008a; Takezawa et al., 2008b; Takezawa et al., 2010). One model is a culture system utilizing substrata made of tissue/organ sections for histopathology (TOSHI), which was found to conserve both tissue components and microarchitecture in an in vivo environment (Takezawa et al., 2002; Takezawa, 2003). Meanwhile, it is reported that mouse embryonic stem (ES) cells injected into the tail veins of carbon tetrachloride (CCl4) liver-injured mouse were differentiated into hepatocyte-like cells in the host liver (Yamamoto et al., 2003). Therefore, we investigated whether the ES cells could also be differentiated into hepatocyte-like cells when they were cultured on the TOSHI-substrata prepared from livers in various stages after CCl4 administration into mice. Consequently, it was found that the substrata derived from regenerating livers enhanced cell attachment, supported growth as clusters, and induced differentiation into cells expressing albumin, although the substrata from injured livers did not. In particular, the cells cultured on the most proliferative regenerating liver-derived substratum reconstructed the hepatic cord-like structures with bile canaliculus-like aspects in which some binucleated cells were involved, secreted albumin, and expressed cytochrome P450IA1 activity within a few days (Takeuchi et al., 2008; Takezawa et al., 2008; Takezawa et al., 2008b). These data suggest two advantages based on the behavior of ES cells in a culture system utilizing TOSHI-substrata; one is that TOSHI-substratum derived from regenerating livers with high proliferative potential efficiently induced the differentiation of ES cells toward hepatic lineage and another is that ES cells functioned as a sensor recognizing liver toxicity in TOSHI-substratum derived from injured livers after CCl4 administration into mice. Therefore, it is considered that the former would be available for the novel approach of drug discovery to find bioactive factors and the latter provide a new alternative method of animal experiments in toxicology to support drug development.

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A Novel Strategy for Drug Discovery and Development by Analyzing the Behavior of ES Cells Cultured on TOSHI (Tissue/Organ Sections for Histopathology)–Substrata