top of page
How is a mammalian embryo reproducibly shaped?

Just like bird flocks and snowflakes, post-implantation embryogenesis is an extraordinary example of self-organisation. The emergence of higher-order structures whose complexity exceeds the sum of its parts requires a dynamic dialogue with the extracellular environment and the coordination of cellular behaviours in space and time. Hence, studying embryo development in toto is critical to understand the underlying molecular, cellular and morphogenetic principles regulating this process. While we have gained important insights from tractable and optically accessible species such as zebrafish, important questions, such as how mechanical and chemical inputs are integrated in morphogenesis, remain unanswered. Moreover, there is emerging evidence that the regulatory programs and repertoire of cellular behaviours driving morphogenesis differ in mammalian compared to non-mammalian species. For example, axial elongation dynamics differ between mouse and zebrafish, which may be related to differences in e.g. the mechanical forces and the coupling of growth and morphogenesis in mammalian embryos. Such differences illustrate the importance of studying embryo morphogenesis in a mammalian system. In this context, outstanding, yet unanswered questions are: which cell-cell, cell-matrix and tissue-tissue interactions drive mammalian embryo architecture? How are form and fate coordinated? How is developmental variability controlled? In sum, how is a mammalian embryo reproducibly shaped?

Fig. 1. Left: live imaging of the development a trunk-like-structure (TLS). Middle: embryo-like architecture is unlocked in TLS (bottom) compared to gastruloids (top). Right:  3D reconstruction of a TLS carrying fluorescent reporters marking somites (red) and neural tube (cyan),  imaged by light-sheet microscopy.

Image credits: Adriano Bolondi, Leah Haut, Dennis Schifferl, Léo Guignard, Jesse Veenvliet.

In order to fill these knowledge gaps it is useful to investigate self-organised pluripotent stem cell-derived stembryos (embryonic organoids). Stembryos circumvent the challenges posed by the inaccessibility of implanted embryos and can be generated in high numbers. Gastruloids are stembryos that form elongating structures reminiscent of an “embryo without a head” with derivatives of all three germ layers, but with compromised morphogenesis. For example, somitic cells do not condense into somites and neural cells don’t form a neural tube. We discovered that precisely timed addition of a small percentage of an artificial extra-cellular matrix compound (Matrigel) to gastruloids can unlock their morphogenetic potential. The resulting structures form somites (the precursors of bone, muscle and cartilage in the embryo) and a neural tube (that eventually forms the spinal cord). Given their striking resemblance to the embryonic trunk we called these stembryos "trunk-like structures" (Fig. 1; Veenvliet et al., 2020; Veenvliet & Herrmann 2021; Bolondi et al., 2021). 


Fig. 2. The morphogenetic potential of gastruloids is unleashed in trunk-like structures (TLS), resulting in higher-order embryo-like architecture. We will exploit the scalability, tractability and accessibility of stembryos to deconstruct the design principles that sculpt the embryo. To this end, we will directly compare molecular, cellular and morphogenetic processes in gastruloids and TLS. Moreover, we will develop tools to learn from variation and utilize the resulting insights to build better, more complete stembryos with higher modularity and reproducibility. We will always keep in mind that the embryo is the "ground state" truth.

In contrast to their natural counterpart stembryos are easy to access, track, manipulate and scale, which positions them as a powerful platform to quantitatively interrogate developmental processes across spatial and temporal scales. With #teamstrembryo, we will combine these general advantages of stembryos with the unique possibility to directly compare expression and morphogenetic dynamics in stembryos with different levels of morphological complexity (Fig. 2). Through this we will define and dissect the cellular interactions that shape the (st)embryo and show how these impact cell fate decisions. In addition, we will exploit the accessibility and scalability of the system to learn from variation by exploring the stembryo morphospace using multi-modal approaches with the embryo as a "ground truth" reference. We will use the resulting insights to control and steer stembryo development. Together with the implementation of design principles of the embryo, this will result in better, more complete and more reproducible stembryos. Finally, we attempt to generate human trunk-like-structures to enable the study of the molecular, cellular and morphogenetic processes that shape the human post-implantation embryo in health and disease.

Dissecting the information modules that shape the (st)embryo
Which cellular interactions drive mammalian embryo-like architecture? How are forces, form and fate coordinated? By direct comparison of stembryos with different levels of morphogenetic complexity, we define the inputs that sculpt the embryo across space and time.
Learn from variation

The embryo is always right. The stembryo is often wrong. We develop frameworks to leverage variation by backtracking causative developmental dynamics. This delivers novel biological insights and provides means to control and steer development in a dish.

Fig. 3. In the absence of in vivo constraints stembryos can settle into different morphological states (e.g. unilateral somites (left panel) or bilateral somites (right panel)). Understanding why some stembryos model the embryo ground truth better than others can teach us why - to quote Viktor Hamburger - the embryo is always right. We will identify and systematically interrogate the bifurcation points, the points at which small changes in the culture conditions change the morphological outcome. Image credits: Adriano Bolondi, Dennis Schifferl, Jesse Veenvliet.

Building better models

We implement design principles of the embryo to build better stembryos. Moreover, we aim to establish human stembryos from pluripotent stem cells to study the molecular, cellular and morphogenetic processes that shape the human embryo in health and disease. 


Fig. 4. Building better stembryos. We will implement in vivo design principles to generate more complete stembryos and increased reproducibility. By direct comparison of the stembryos with the embryo, we will define what drives deviations of the embryonic ground truth. We will then implement data-driven designs to guide the optimization of models of mammalian embryo development. Moreover, we aim to generate human trunk-like-structures from human pluripotent stem cells, to enable the study of human post-implantation development across spatial and temporal scales.

bottom of page