Cell fate choice and morphogenesis in stem cell models of early human development

Abstract

Human embryonic development, which starts with a single cell, is remarkable in its ability to perform the following phenomena: first, the generation of hundreds of different types of cells, each with a unique function and gene expression pattern, and second, the assembly of these cell types into the large-scale structures of tissues and organs. In the past decade, human embryonic stem cells (hESCs) have shown tremendous promise as models for human development in their guided formation of various cell types and their self-organization into shapes resembling organs. Here, I use human stem cells to study two fundamental questions about human embryogenesis. In my first project, my collaborators and I investigate how stem cells lose competence for alterative fates as they differentiate toward a particular cell fate. We specifically investigate the first decision of pluripotent hESCs and measure their decreasing competence to form the mesendoderm cell type as they are differentiated toward the ectoderm lineage. We find that, as cells progress toward ectoderm, we can predict and genetically tune its competence to form mesendoderm by overexpressing key genes inferred from transcriptome and chromatin accessibility data from pre- and post-competence-loss cells. In my second project, we develop a high throughput method to wholly perturb hESC-derived organoids, allowing us to study hundreds of individual genes in tissue-wide processes like morphogenesis. We apply our method to the study of anterior neural tube (future brain) folding, and find that three neural transcription factors (ZIC2, ZNF521, and SOX11) are required for proper folding in the human model.