Self-organizing multicellular systems derived from mouse embryonic stem (mES) cells called gastruloids, which previously have been shown to mimic critical events of mammalian gastrulation, have been shown by Institut Pasteur researchers to have highly intrinsic reproducible patterns of gene expression and growth dynamics. These properties enable the three-dimensional self-assembling structures to serve as a powerful tool for quantitative studies of mammalian development and various other biological processes in vitro.

The research article, “Precise and scalable self-organization in mammalian pseudo-embryos,” was published in Nature Structural & Molecular Biology.

In vitro replication of fundamental developmental processes

Multicellular development involves precisely arranging cellular characteristics and body sizes in space and time. The process of gastrulation plays a crucial role in the development of the body plan and the subsequent formation of asymmetrical body axes. During this particular stage, the synchronization of gene expression results in consistent patterns across individuals despite the inherent variability in the molecular processes involved in gene regulation. One notable outcome of this level of precision is the ability to scale gene expression patterns based on the size of the system. Quantitative reproducibility, precision, and scaling assessments have been achieved in systems like worms, flies, and frogs but have been limited in mammalian systems.

The impracticality of achieving these findings in mammals in vivo necessitates using in vitro systems to ensure experimental accessibility and manipulability. The recent advancements of in vitro models, namely gastruloids derived from mES cells, offer promising opportunities for studying mammals. These pseudo-embryos, which are three-dimensional, replicate critical stages of mammalian gastrulation by exhibiting self-organized patterns. They can be grown in large quantities, making them suitable for quantitative methodologies. However, concerns have been raised regarding the reproducibility of these systems at molecular and cellular levels.

Precise and scalable self-organization in mammalian gastruloids

Mélody Merle, Leah Friedman, and Corinne Chureau researched the intrinsic reproducibility of gastruloid self-organization, specifically analyzing growth dynamics and gene expression patterns. The researchers observed significant control over gene expression along the primary body axis, with pattern boundaries accurately located at the cellular level. Furthermore, cells at each point along the pattern produce the same quantity of gene product in absolute units.

These levels of reproducibility and precision remain consistent for gastruloids grown in parallel from the same population of cells. Additionally, gastruloid growth scales precisely with the initial number of seed cells.

The remarkable reproducibility, precision, and scalability demonstrated by gastruloids have significant biological implications. They challenge our conventional understanding of mammalian development, hinting at the precise regulation of developmental features, such as gene expression patterns, during self-organized processes. The inherent replication and accuracy of synthetic systems, akin to in vivo systems such as ascidians, worms, flies, and frogs, broadens the potential for sophisticated engineering applications in the realm of organoids and, more broadly, cell aggregates.

These findings suggest that reproducibility and scaling, evident in developing embryos and synthetic structures like gastruloids may represent context-independent properties. This study’s results provide insight into the complexities of developmental accuracy, consistency, and size adjustment in a mammalian system, indicating that these phenomena may be essential characteristics of multicellularity. 

While the study highlights the potential of gastruloids as a model system, it has limitations. Gastruloids, while powerful tools, are not identical to in vivo embryos, and thus there are aspects of development they cannot fully replicate. For instance, gastruloid shape is not consistently reproducible. Gastruloid length, which is a component of shape, exhibits more variation at 120 h compared to pattern boundary positions. Additionally, translating these findings to in vivo contexts remains a challenge. Nonetheless, the study underscores the value of using in vitro systems as accessible and controllable models for studying development.

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