The connection between "stemness" and aldehyde dehydrogenase [ALDH] activity is most likely, the link is through the retinoids. Retinol is vitamin A. This essential nutrient is oxidized by cellular enzymes into retinaldehydes, which in turn is oxidized by ALDH into retinoic acids. Retinoic acids come in a variety of slightly different chemical forms, but all of them share one essential feature: They can bind to families of transcription factors [also sometimes called, perhaps unfortunately, retinoid receptors] and change the affinity of these transcriptions factors for “retinoid responsive elements” in gene promoters. There are many retinoid responsive gene promoters in the genome, and as a result, retinoic acids can, through their effects on transcription factors, simultaneously up regulate and down regulate large numbers of genes. Going back up the chain, again, this means that ALDH, by synthesizing retinoic acids, plays a major role in controlling large blocks of genes. Significantly, some developmentally important control genes such as Hox genes, that themselves switch large blocks of regulatory activity are controlled by retinoids, and synthesis of ALDH is regulated by some Hox genes. Thus, ALDH seems to be in the middle of gene programs that are active in regulatory and developmental processes, and to the degree that a stem cell state can be defined by the level of gene products expressed in a cell, ALDH is a major player in defining this state.

The potent effects of retinoids in developmental systems are well established. All-trans retinoic acid, for example, is a powerful morphogenetic signal in the formation of the nervous system. Mice in which ALDH has been knocked out die during neural tube closure, and vitamin A deficiency is lethal or severely detrimental to the developing human nervous system. In chickens, a gradient of retinoic acid synthesis, generated from a gradient in ALDH expression, is established across the developing retina, and the retinoic acid controls the formation of the retinal [which is actually an extension of brain] tissue. ALDH has long been known to be enzyme that renders hematopoietic stem cells resistant to alkylating agents such as cyclophosphamide; this observation, in fact, is the basis for the development of the ALDAGEN core technology. Developmentally, retinoids can drive differentiation of blood cells down different lineages, and, in fact all-trans retinoic acid is used as a therapeutic agent to differentiate certain types of leukemia. The importance of retinoids in defining the stem cell state appears to have emerged very early in vertebrate evolution, as very primitive, pluripotential stem cells that can give rise to all cell lineages in tunicates have now been shown to express high levels of ALDH.