System biology and waddington landscape

In this talk, I presented our work on pattern formation during human embryonic stem cell (hESC) development, the subject of my master’s thesis at Sharif. We proposed a multicellular mathematical model for pattern formation during the in-vitro gastrulation of human ESCs. This model enhances the basic principles of the Waddington epigenetic landscape with cell-cell communication, which enables us to describe how the pattern and tissue formation occurs in the course of development.

Inside one cell, BMP4 activates itself and Noggin while Noggin inhibits BMP4: two ODEs with eight fitted parameters. Across the colony, secreted BMP4 and Noggin diffuse between cells, and the fate territories (CDX2+ at the edge, then SOX17+, BRA+ and SOX2+ in the centre, after Warmflash et al. 2014) emerge from the edge inward.

How the model works. Every cell carries the same minimal gene circuit: BMP4 activates itself and its own inhibitor Noggin, and Noggin inhibits BMP4. On its own, a single cell can oscillate indefinitely; once cells are coupled through diffusion of the secreted BMP4 and Noggin, they settle into stable fates. In a micropatterned colony the pattern is initiated at the boundary and spreads towards the centre, reproducing the concentric germ-layer rings seen experimentally. The same model also explains why very large colonies (around 3 mm) show spotted rather than ring-shaped territories, and how the pattern responds to altered culture conditions and micropattern diameters.

The work was published in Bioinformatics (2019), and the simulation code is on GitHub.

You can download the slides.