A novel self-organizing embryonic stem cell system reveals signaling logic underlying the patterning of human ectoderm

Abstract

During development, the ectoderm is patterned by a combination of BMP and WNT signaling. Research in model organisms has provided substantial insight, however, there are currently no systems to study this patterning in humans. Further, the complexity of neural plate border specification has made it difficult to transition from discovering the genes involved to deeper mechanistic understanding. Here, we develop an in vitro model of human ectodermal patterning, in which hESCs self-organize to form robust and quantitatively reproducible patterns corresponding to the dorsal-ventral axis of the embryo. Using this platform, we show that the duration of endogenous WNT signaling is a crucial control parameter, and that cells sense relative levels of BMP and WNT signaling in making fate decisions. These insights allowed us to develop an improved protocol for placodal differentiation. Thus, our platform is a powerful tool for studying human ectoderm patterning and for improving directed differentiation protocols.

Axis Specification in Zebrafish Is Robust to Cell Mixing and Reveals a Regulation of Pattern Formation by Morphogenesis

“…During gastrulation, a complex series of cell movements progressively shape the early embryo and act concomitantly with the progressive specification of cells along the anterior-posterior axis. The timing of exposure to Wnt and BMP signals is essential for patterning ectodermal derivatives [ 26 , 27 , 28 , 29 ], yet how this temporal modulation of these signaling pathways is achieved is unknown. One possibility could be that gastrulation movements are themselves important for regulating signal exposure, by spatially separating cells expressing signals and their secreted inhibitors.…”

“…Whether the absence of forebrain specification in pescoids is due to the lack of additional extra-embryonic signals or due to the fact that additional morphogenetic events are required to separate organizer-derived signals is an open question. The requirement for a precise temporal modulation of BMP and Wnt activity during the specification and patterning of the ectoderm is well known [ 26 , 27 , 28 , 29 , 33 , 34 ]. Here, we provide evidence for a role of global tissue morphogenesis in regulating the exposure to ligands and secreted inhibitors of these pathways, potentially providing a mechanism by which patterning and morphogenesis is coordinated during gastrulation.…”

Amniogenesis occurs in two independent waves in primates

“…(legend continued on next page) ll OPEN ACCESS Article 2019). Genes characteristic for the AME/NNEC lineage included known markers ISL1 and BMP4 (Britton et al, 2019;Tchieu et al, 2017;Yang et al, 2021). Furthermore, other genes such as GABRP, TFAP2B, and WNT6 were expressed at later stages of AME/NNEC development (cyAME-L3 and hsNNEC2).…”

Pluripotent stem cell models of early mammalian development

“…In these experiments, cells develop as coherent groups in defined relative proportions, with few heterogeneities; often organised into concentric rings of different cell types. Micropatterned cultures are a useful tool to decipher the signalling logic associated with the early spatial organization of tissue primordia [15] and have highlighted the importance of signal dynamics [16][17][18], boundary conditions [11], mechanics, geometry [13,19,20] and community [21] in cell fate decisions. In an extension of this work, the radial symmetry observed with circular micropatterns could be broken by applying an asymmetric flow of signals and inhibitors in a situation that mimics the embryo [22].…”