Virtual cells in a virtual microenvironment recapitulate early development-like patterns in human pluripotent stem cell colonies
Himanshu Kaul, Nicolas Werschler, Ross D. Jones, Mona Siu, Mukul Tewary, Andrew Hagner, Joel Östblom, Daniel Aguilar‐Hidalgo, Peter W. Zandstra
Abstract
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.