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Stem cell models of the human embryo

The first three weeks of human embryo development is when the specialization of cells begins, the embryo implants into the uterus, and gastrulation breaks the embryonic symmetry setting the blueprint for organ development. The molecular and cellular details underlying these developmental milestones are quite poorly understood, in part owing to the unique nature of human development and in part to the technical and ethical challenges of studying human embryogenesis. We develop stem cell models of the human embryo finally to access these long-time elusive steps of human development. Our assembled stem cell embryoid was among the first to model human embryo attachment and the downstream cell specification in early gastrulation.

We now use embryo models to elucidate the chemical signaling and the biomechanics of embryo implantation and placenta development, so to map out the detailed single cell atlas at the embryo-maternal interface, and to investigate the basic rules of embryonic tissue patterning in human gastrulation.

Implications to human health: Embryo implantation is the most important bottleneck of pregnancy and failures in the first embryonic milestones are the leading cause of infertility, recurrent pregnancy loss, and many other early pregnancy disorders. Elucidating the molecular causes of embryo implantation will help devise new early diagnostic and therapeutic strategies aimed at improving the reproductive health of women and all humans with the female reproductive system.

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New paradigms in human organoids

Mapping the detailed genomic and epigenomic networks that drive human organogenesis is one of the most desired goals of contemporary biology. It will not only allow us to build in vitro models of disease, but one day open doors to growing on-demand and patient-specific organs in a lab. In fact, we are getting very close to this goal. With the recent explosive progress in stem cell biology, we can now create miniature versions of human organs, called organoids, by growing pluripotent stem cells in three-dimensional matrices and exposing them to specific chemical signals. However, despite the cellular diversity of these tissues, organoids are still far from human organs. Furthermore, the vast majority of organoid research is focussed on the brain or the intestine, perhaps because these organs form at the extreme ends of the body, thus requiring somewhat more easily employable signaling requirements, high or no signaling.

We recognize two key challenges in the field of synthetic organogenesis. The first is correctly patterning organoids to recreate more accurately the spatial signaling hierarchy in organogenesis. The second is engineering pure regionally specialized tissues such that can be used in regenerative medicine. To address these challenges, we employ a combination of tissue engineering and CRISPR gene editing to create the realistic organ-forming signaling gradients and to control precisely the genetic circuitry that instructs cell identity and location within an organ. Our goal is to generate organoids that can recreate organogenesis along portions or entire body axes, revealing clues of how individual organs are specified and spatially segregated, and to map out the single cell atlas of early human organogenesis.

Implications to human health: Developing tools that more accurately differentiate pluripotent stem cells into patterned organ progenitors will create opportunities for using organoids as a renewable patient-specific source of human tissues. Research that aims to bridge the gap between organoids and human organogenesis should be prioritized to advance the potential for regenerative and transplant medicine.

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Patterning rules in mammalian embryogenesis

Signaling pathways that transform the early embryo into defined body plans are remarkably conserved across the animal kingdom. Yet, we always develop into completely differently looking organisms. A human always looks like a human, a mouse always looks like a mouse, and no mouse embryo ever develops into an elephant. It is becoming increasingly clear that beyond a genetic code, there are external cues that influence the way signals interact with the cells and in this way control cell specialization and tissue patterning. We reconstitute early embryonic patterning from stem cells and employ materials with controlled chemical and mechanical properties, single cell profiling, and CRISPR gene editing, to map out the detailed hierarchies in cell fate decisions from early embryo to its organ progenitors. We also investigate the influence of external factors on these decisions, ultimately to figure out how the embryo attains its unique shape.