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

Himanshu Kaul; Nicolas Werschler; Ross D Jones; M Mona Siu; Mukul Tewary; Andrew Hagner; Joel Ostblom; Daniel Aguilar-Hidalgo; Peter W Zandstra

doi:10.1016/j.stemcr.2022.10.004

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.

Authors

Himanshu Kaul¹, Nicolas Werschler², Ross D Jones³, M Mona Siu⁴, Mukul Tewary⁵, Andrew Hagner², Joel Ostblom⁵, Daniel Aguilar-Hidalgo³, Peter W Zandstra⁶

Affiliations

¹ School of Engineering, University of Leicester, Leicester, UK; Department of Respiratory Sciences, University of Leicester, Leicester, UK.
² School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
³ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
⁴ Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
⁵ Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
⁶ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada. Electronic address: peter.zandstra@ubc.ca.

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.

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

Grants and funding

FDN-154283/CIHR/Canada