Neuroepithelial organoid patterning is mediated by Wnt-driven Turing mechanism

Abstract

Cell patterning in epithelia is critical for the establishment of tissue function during development. The organization of patterns in these tissues is mediated by the interpretation of signals operating across multiple length scales. How epithelial tissues coordinate changes in cell identity across these length scales to orchestrate cellular rearrangements and fate specification remains poorly understood. Here, we use human neural tube organoids as model systems to interrogate epithelial patterning principles that guide domain specification. In silico modeling of the patterning process by cellular automata, validated by in vitro experiments, reveal that the initial positions of floor plate cells, coupled with activator-inhibitor signaling interactions, deterministically dictate the patterning outcome according to a discretized Turing reaction-diffusion mechanism. This model predicts an enhancement of organoid patterning by modulating inhibitor levels. Receptor-ligand interaction analysis of scRNAseq data from multiple organoid domains reveals WNT-pathway ligands as the specific inhibitory agents, thereby allowing for the experimental validation of model predictions. These results demonstrate that neuroepithelia employ reaction-diffusion-based mechanisms during early embryonic human development to organize cellular identities and morphogen sources to achieve patterning. The wider implementation of such in vitro organoid models in combination with in-silico agent-based modeling coupled to receptor-ligand analysis of scRNAseq data opens avenues for a broader understanding of dynamic tissue patterning processes.

Symmetry-breaking in adherent pluripotent stem cell-derived developmental patterns

“…If these diffusible molecules couple in a Turing-like Activator (A)-Repressor (B) form, such that A activates the production of B, and B limits the production of A, concentration profiles of these molecules can self-organize within their spatial domain (Turing 1952). Although these models can simulate conditions for spontaneous symmetry breaking (Ishihara and Tanaka 2018; Sozen, Cornwall-Scoones, and Zernicka-Goetz 2021), they have so far only been used to explain the formation of the observed centro-symmetrical patterns in in-vitro adherent PSC colonies (Tewary et al 2017; 2019; Brassard and Lutolf 2019; Fattah et al 2021; Kaul et al 2022) and to mimic polarized patterns under asymmetric induction conditions in micro-fluidic systems (Manfrin et al 2019).…”