Patterning the embryonic ectoderm gives rise to defined domains of progenitors for cell types as diverse as neurons, neural crest, placodes and epidermis. Studies in model organisms have defined many of the molecular players that guide patterning, but the extent to which a similar logic applies in humans remains unclear. Now, Aryeh Warmflash, George Britton and colleagues tackle this problem by harnessing the self-organising capacity of human embryonic stem cells (hESCs) confined to micropatterned surfaces. Transient inhibition of Nodal signalling in hESCs induces an ectodermal progenitor state that can be further guided down neural or non-neural routes (with continued Nodal inhibition or addition of BMP4, respectively). In micropattern-confined colonies, Nodal inhibition followed by BMP4 addition promotes the formation of self-organised radial territories of ectodermal cell fates. Placodal domains are expanded when endogenous WNT signalling is inhibited, at the expense of the neural crest domain (where WNT activity is highest). BMP4 signalling initiates and controls the size of the surface ectoderm domain, the decision between neural crest and placodal fates is determined by the relative levels of BMP and WNT signalling, and, finally, a combinatorial logic of WNT and BMP signalling drives neural crest specification. This powerful system not only illuminates human ectodermal patterning but can also guide future efforts to derive pure populations of subsets of ectodermal cell fates.
