Environmental influences govern cell fate choice of multipotent neural crest cells

During embryonic development, cells from at least four distinct progenitor pools come together to form the heart. Congenital heart disease can result from a failure of this process, particularly if cells from a progenitor pool are abnormal or missing. One of these pools is the cardiac neural crest (CNC). Neural crest cells emigrate from the edge of the neural tube during neurulation, and populate a wide variety of structures within the embryo, differentiating to more than 30 different cell types depending on their final location¹. The neural crest was first described in 1850ish, but it was not until the early 1980s that Nicole Le Douarin and collegaues described the derivatives². The CNC are a subset of these cells that were first described by Margaret Kirby and colleagues³. These cells arise at the level of in the caudal hindbrain, and contribute to the pharyngeal arch arteries, cardiac outflow tract septum and valves. Since the discovery of the neural crest over 150 years ago, one key question has been “how can a single cell type contribute to so many different cell types”. Debate has focussed on whether these cells are totipotent, multipotent or have a pre-determined fate; and how much the local environment of the final destination affects differentiation.

Marianne Bronner and Scott Fraser, working in the late 1980s, used vital dye injection and lineage tracing to provide the first evidence that at least some neural crest cells were multipotent progenitor cells⁴. Over the past two decades, genetic studies have defined the gene regulatory networks required for: (i) neural crest specification; (ii) epithelial-to-mesenchyme transition; (iii) migration; and (iv) differentiation. Most recently, the advent of single cell transcriptomics has confirmed the genetic conclusions and provided support for the classical germ layer model that neural crest cells first adopt a neuroectoderm fate at specification, and then re-activate multipotency genes as they migrate away from the neural tube⁵. However, these studies have not shed light on how these multipotent cells “decide” where to migrate to and what sort of cell to differentiate into once they reach their target tissue. Therefore, the Bronner group has re-visited this issue using the latest single cell imaging techniques⁶.

To follow single cells in vivo, Tang et al used retroviral infection of chick embryos in ovo, followed by photoconversion of single cells. These cells were followed by post hoc clonal analysis or by live imaging. They focussed on examining the difference between two populations of NC (cardiac and posterior vagal) that arise from immediately adjacent portions of the caudal hindbrain, and were thought to always contribute to different tissues. Intriguingly, Tang et al found that cells from the two locations initially migrate at random, with individual cells from different starting locations intermixing rather than being restricted to separate streams. However, once cells enter a stream, specific signalling cues guide the multipotent cells towards specific organs. Thus, for example, some of the “cardiac” NC cells end up in the enteric nervous system. In conclusion, these results suggest that NC cells are indeed a multipotent stem cell population, with signals from the local environment controlling their final location and cell fate.