Stem Cell Biology in Toxicology. Trosko J.E., Kwan K., Upham B., Halgren R.G., Zacharewski T.R. and Chang C.C.

Stem cells are defined as cells that can divide asymmetrically to give rise to a daughter that is committed to terminally differentiate and another daughter that can maintain "stemness". In addition, they have the potential to divide symmetrically to expand their numbers. Toti-potent stem cells give rise to pluri-potent stem cells, which, in turn can give rise to committed progenitor cells. Since the demonstration of embryonic-derived pluripotent stem cells, as well as from adult tissue, the question arises, "Is there a differential sensitivity to toxicants between the stem cell, its committed progenitors and the terminally-differentiated daughters"? The stem cell theory of carcinogenesis implies that these cells are the target cells for carcinogenic initiation. Until recently, little attention has been given to the potential differential sensitivities of the stem cell family. In the usual molecular and biochemical studies (including that of the DNA microarray technology) of toxic effects on organs/organisms or of comparative studies of normal versus diseased tissues, DNA, RNA and proteins are extracted from the whole tissue containing few stem cells, and many committed progenitor and terminally differentiated cells. If a toxicant differentially affects the cells of the stem cell lineage, the examination of the combined DNA lesions, expressed genes and protein products of all of these cell types could mask critical events occurring only in the "target" or stem cells. Human breast epithelial, human kidney, human neuronal and human pancreatic stem cells do not have functional gap junctional intercellular communication (GJIC). Exposure to c-AMP-inducing agents triggers GJIC and differentiation. Agents that block GJIC appear to block differentiation. The use of epigenetic toxicants on human stem cell systems could providenovel insights into their contribution to in vivo toxic effects, since their response to toxicants could differ when compared to differentiated cells with drug metabolizing systems.