Endless Possibilities: Stem Cells and the Vision for Toxicology Testing in the 21st Century

Abstract

The National Research Council's (NRC) toxicity testing vision lays out a bold future for our field. It depends heavily on computational algorithms based on the latest knowledge of cellular biochemistry and protein interaction pathways, exposing human cells to novel compounds in vitro, and being able to understand the changes seen. At the same time, significant strides are being made in our understanding of the control, production, and "behavior" of stem cells. While stem cells offer seemingly limitless possibilities for regenerative medicine, they have already delivered new assays to predict embryo-fetal developmental toxicity in vitro. In addition to providing a model of cells undergoing differentiation and proliferation, stem cells will play a major role by giving rise to many of the differentiated cell types on which this new vision depends. These will not be pure populations of single cell types but mixtures of cells much more representative of tissues in vitro. Moving from cells alone in a culture dish toward the more physiological condition of multiple cell types being able to interact to maintain homeostasis in the face of a disequilibrating force (like a toxic exposure) will lead us toward more useful and correct predictions of in vivo toxicities. Despite the seemingly insurmountable hurdles, persistence and creativity are on our side. We expect that a long series of successive iterations of predictive models will eventually yield a working process that approximates the NRC's vision and delivers on the promise of faster evaluation of chemicals with reduced animal use.

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

“…General Similar efforts should be extended for the (favorably human) EST (Kleinstreuer et al, 2011;West et al, 2010). The obvious potential of combing stem cell methods with Tox-21c approaches was stressed earlier (Chapin and Stedman, 2009). This extends from embryotoxicity to other areas such as male fertility (Krtolica and Giritharan, 2010) and to link toxicity related biomarkers uncovered using hES cells with the PoT concept.…”

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“…So, the total message examined is the result of expression of all these types of cells. This point has been studied as they titled as: ''Traditional microarrays''; which can neither distinguish between variations in gene expression resulting from an actual physiological change versus differences in cell-type frequency nor identify the contributions of different cell types to the total measured gene expression [15].…”

Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century

“…Scientists have suggested the development and use of more humane and better, science-based alternative approaches in toxicology for many years (Goldberg, 1983;Zbinden, 1990a,b;Balls, 1998;Hartung, 2001;Coecke et al, 2007). However, it seems that support for the proposed paradigm shift in toxicology is currently growing, considering the generally supportive comments on the vision (Seidle and Stephens, 2009;Chapin Therefore, cell models need to be well characterized and maintained under optimized and standardized culture conditions. Although 3D models are increasingly used, most commercial toxicity endpoints are still adjusted to monolayer cultures in multi-well plates.…”

“…The promise is that human cells can predict more accurately the response of the human body to chemicals than animal cells can. Another important advantage of human cells is their potential to reveal human susceptibility factors for disease or toxicity (Chapin and Stedman, 2009 (Leist et al, 2008). Human embryonic stem cells are isolated from the inner cell mass of the blastocyte at the stage of embryonic development when implantation occurs (Bongso et al, 1994).…”