Abstract

Embryonic development requires multi-scale coordination of tissue morphogenesis, cellular behaviours, and gene expression to ensure highly reproducible differentiation outcome at the systems level. A deep understanding of the feedbacks that govern such robustness requires the study of the processes that pattern and shape the embryo in live specimens, in toto, across spatial and temporal scales. In mammalian embryogenesis, this remains a major challenge as the embryo develops in utero, precluding easy accessibility. These impediments can be overcome by coaxing pluripotent stem cells to form three-dimensional embryonic organoids (or stembryos) in vitro. Gastruloids are stembryos that break symmetry, elongate and self-organise the major body axes, but lack the stereotypical architecture of the embryo. We have shown that the latter can be unlocked by precisely timed addition of an extracellular matrix, resulting in trunk-like-structures (TLS) that molecularly and morphologically resemble the core part of the embryonic trunk. In contrast to its in vivo counterpart, these stembryos are easy to access, track, manipulate and scale. I will explain how we leverage these unique properties to identify minimal sets of inputs necessary to pattern and shape the mammalian embryo through controlled modulations of the system. Moreover, I will discuss novel frameworks we have developed that allow us to connect transcriptional, cellular and morpho-states in space and time, and how these help us to uncover the design principles of regulative development during critical windows of mammalian embryo morphogenesis.