Toxic stress prioritizes and imbalances stem cell differentiation: implications for new biomarkers and in vitro toxicology tests

Abstract

This hypothesis and review introduces rules of stem cell stress responses that provide biomarkers and alternative testing that replaces or reduces gestational tests using whole animals. These rules for the stress responses of cultured stem cells validate the organismal strategy of the stress response and show that it emulates what must happen if the conceptus implants during a response to stress in vivo. Specifically there is a profound threshold during a stress dose response where stem cell accumulation is significantly reduced. Below this threshold stress enzymes manage the stress response by converting anabolic to catabolic processes and by suppressing apoptosis, without affecting differentiation. However above this threshold the stem cell survival response converts to an organismal survival response where stress enzymes switch to new substrates and mediate loss of potency factors, gain of early essential differentiated lineages, and suppression of later essential lineages. Stressed stem cells ‘compensate’ for lower accumulation rates by differentiating a higher fraction of cells, and the organismal survival response further enhances adaptation by prioritizing the differentiation of early essential lineages. Thus compensatory and prioritized differentiation and the sets of markers produced are part of a response of cultured embryos and stem cells that emulate what must happen during implantation of a stressed gestation. Knowledge of these markers and use of stressed stem cell assays in culture should replace or reduce the number of animals needed for developmental toxicity and should produce biomarkers for stressed development in vitro and in vivo.

Keywords:

• differentiation
• stem cells
• stress
• stress enzymes
• toxicology

Acknowledgments

We thank Mike Kruger for advice on statistical analysis on optimizing toxicological assays. We are also indebted to Dr. Michael Diamond for helpful discussion and criticisms of the manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This was supported by a grant to DAR from NICHD, NIH, (R01 HD40972A, 1R03HD061431 02) and from the Office of the Vice President for Research at Wayne State University.