Understanding how stem cells function in the creation and maintenance of biological shape is fundamental to three main areas of biomedicine: birth defects, which result from failure to build appropriate structures during embryonic development; regeneration after injury or disease, which requires the proper shape of the damaged structure to be rebuilt in adulthood; and, finally, cancer, which can be seen as a failure to obey the patterning cues that continuously act to impose three-dimensional order against neoplasia and aging. The neural crest is a key population of stem cells that migrate throughout the embryo and contribute to structures such as the heart, face and skin. Neurocristopathies, which are defects in neural crest development, form an important class of congenital defects.
Although the genetic and biochemical signaling pathways that regulate the conversion from normal developmental patterning to cancer have been intensively studied, an important class of signals remains poorly understood: endogenous bioelectric cues produced by ion channels and transmembrane voltage gradients.
Owing to their ease of manipulation and relative transparency, Xenopus laevis embryos are a particularly convenient model for understanding the signals directing neural crest cells and their progeny. To determine how changes in membrane voltage regulate cell behavior and interactions in vivo, the authors target a population of cells expressing the glycine-gated chloride channel (GlyCl). By opening the channel pharmacologically and manipulating ion levels to hyperpolarize or depolarize these cells, they show that GlyCl-expressing cells can trigger a neoplastic-like phenotype in an important class of neural crest derivatives – the pigment cells known as melanocytes. The GlyCl-expressing ‘instructor’ cells trigger hyperproliferation, and cause increased dendricity and invasiveness into neural tissues, blood vessels and gut. Crucially, the induction of this metastatic phenotype occurs at long range and is mediated by serotonergic signaling.
Implications and future directions
This work demonstrates that the bioelectrical state of specific cells in the host can trigger the stem cell to neoplastic cell transition in pigment cells, resulting in a phenotype that is similar to that of metastatic melanoma. Crucially, the relevant signal is not tied to GlyCl per se, or even chloride, but is truly carried by a physiological parameter – voltage. These data reveal a new role for ion flow and serotonergic signaling in melanocyte regulation, with potential uses in the treatment of vitiligo and melanoma. Furthermore, they uncover a newly identified population of ‘instructor’ cells (characterized by GlyCl expression) that can control the fate of neural crest derivatives with exquisite specificity. The ability to modulate membrane voltage without the need for gene therapy, and the identification of cell types that can direct the function of stem cells, are powerful approaches through which to better understand and address the in vivo control of patterning in cancer, the regenerative response and the repair of birth defects.