Map of 2D Gastruloid Morphospace
This plot was generated from a high-throughput drug screen conducted on a stem cell model of human gastrulation, the 2D gastruloid. In this screen, 210 compounds were used to perturb BMP4-initiated gastruloids, and the resulting cell fate decisions were captured with single-cell resolution. To analyze the data, we employed t-SNE (t-Distributed Stochastic Neighbor Embedding) for dimensionality reduction, followed by a custom clustering algorithm to identify distinct morphological phenotypes.
Each color corresponds to a different phenotype, with red, pink, and purple clusters representing failure modes of gastrulation. The red cluster is characterized by BRA overexpression, the pink by loss of radial symmetry and excessive cell death, and the purple by the absence of BRA expression. Notably, many known teratogens, such as Isotretinoin, are found in the purple cluster. We further tested additional compounds from this cluster, such as Nirogacestat and Ulixertinib, using a zebrafish teratogenicity assay, where both were identified as teratogens. This underscores the platform's potential for high-throughput, human-specific teratogen screening.
The remaining clusters represent variations in canonical cell patterning, where cells organized into radially patterned germ layers. Within this region, we observed that cell density predominantly influences the width of the mesoderm (BRA) band, with higher densities leading to a narrower band.
By hovering over each point on the plot, you can view the corresponding colony image and the drug treatment applied. You can also sort the plot by drug type, cell density, drug target, and drug pathway with the buttons on the right. Drug target and pathway information are based on the information provided by Selleck Chem (Stem Cell Signaling Compound Library, Cat#: L2100). This interactive feature provides a deeper understanding of the morphological phenotypes and their relationship to the various perturbations, offering insights into how different compounds influence cell fate decisions and tissue patterning in the 2D gastruloid.
Highlighted Publications
Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control. Maxwell Z. Wilson, Pavithran T. Ravindran, Wendell A. Lim, Jared E. Toettcher. Molecular Cell. (Download PDF)
