Virtual cells in a virtual microenvironment recapitulate early development-like patterns in human pluripotent stem cell colonies

Stem Cell Reports. 2023 Jan 10;18(1):377-393. doi: 10.1016/j.stemcr.2022.10.004. Epub 2022 Nov 3.


The mechanism by which morphogenetic signals engage the regulatory networks responsible for early embryonic tissue patterning is incompletely understood. Here, we developed a minimal gene regulatory network (GRN) model of human pluripotent stem cell (hPSC) lineage commitment and embedded it into "cellular" agents that respond to a dynamic morphogenetic signaling microenvironment. Simulations demonstrated that GRN wiring had significant non-intuitive effects on tissue pattern order, composition, and dynamics. Experimental perturbation of GRN connectivities supported model predictions and demonstrated the role of OCT4 as a master regulator of peri-gastrulation fates. Our so-called GARMEN strategy provides a multiscale computational platform to understand how single-cell-based regulatory interactions scale to tissue domains. This foundation provides new opportunities to simulate the impact of network motifs on normal and aberrant tissue development.

Keywords: agent-based model; development; digital twin; ectoderm; endoderm; gastrulation; gene regulatory network; mesoderm; multiscale model; reaction diffusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Endoderm
  • Gastrulation / genetics
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Humans
  • Mesoderm
  • Pluripotent Stem Cells*
  • Signal Transduction