Stem cell-grown pseudo-embryos offer new insights into embryogenesis

Researchers from EPFL and the University of Geneva (UNIGE) have made significant strides in investigating the early-stage development of mouse embryos through a unique approach. Rather than relying on animal models, the team conducted their research using pseudo-embryos cultivated in the laboratory from stem cells.

Similar to the way cold cases can be solved with the aid of DNA fingerprinting, scientists are now equipped with new cellular models that allow them to revisit research questions previously unanswerable with animal models alone. These “pseudo-embryos,” or embryoids, offer a promising avenue for unraveling the intricacies of embryogenesis—the process by which embryos develop.

Professor Denis Duboule, who oversees EPFL’s Laboratory of Developmental Genomics and holds a professorship at The Collège de France in Paris, is a seasoned expert in this field. Over the course of three decades, he has delved into the mouse genome to comprehend the fundamental mechanisms governing mammalian development. The concept of pseudo-embryos fills him with enthusiasm as they mirror the structure and development of embryos, thereby facilitating a deeper understanding of embryogenesis.

On June 15th, Duboule’s team published a paper in Nature Genetics that showcased the results of their groundbreaking study. Notably, this research marked the first time in Duboule’s career that he conducted a study without relying on animal models, highlighting the potential of pseudo-embryos as a powerful tool in scientific exploration.

The internal clock regulating embryo development

The development of early mammalian embryos follows a specific pattern along the anterior-posterior axis, with the head forming first and subsequent stages progressing towards the tail. In humans, each stage takes around five hours to develop, while in mice, this process is accelerated to approximately 90 minutes. Researchers at Professor Duboule’s lab have dedicated their efforts to understanding how Hox architect genes, which confer identity to each stage (such as neck vertebrae or the emerging tail in mice), are activated according to a precise schedule dictated by an internal clock.

The intriguing aspect has been unraveling how a mechanism that imposes timing on linear DNA strands could have naturally evolved. Professor Duboule notes that this mechanism resembles a transistor, emitting a signal every 90 minutes in mice. Studying this phenomenon using animal models has been challenging because the mechanism becomes active after the embryo has implanted in the uterine wall, making observation difficult due to the small size of the embryo.

A breakthrough came with the advent of embryoids around a decade ago—cell structures lacking the necessary components to develop into fully grown organisms. In the recent study, Hocine Rekaik, a researcher from Professor Duboule’s lab and the lead author of the paper, utilized embryoids and enriched them to isolate the segment responsible for generating these “stages.” The resulting cell model was simplified yet remarkably realistic.

The role of the CTCF protein was revealed in this process, acting as a blocker on a DNA segment and delaying the expression of the Hox gene located behind it. The activation signal is triggered by the cohesin protein complex. Using animations, the researchers visualized this process occurring in the chromatin of the embryoids, something that would be considerably challenging with real embryos due to increasing complexity and disorder over time. The high concentration of cells in the posterior section of the embryoids provided a more uniform environment for observing the mechanism in action.

Promising new methods

Duboule is thrilled with the recent development of his team’s new model. Not only does it hold great promise for future research, but it is also user-friendly, efficient, and more cost-effective than using animal models. This discovery brings him immense satisfaction, especially because it provides a genuine alternative to relying solely on mice.

“As my career nears its end, having used numerous animals in my lab, I am delighted to witness the emergence of alternative models,” he expresses. “While we may not be entirely ready to eliminate animals from pure research, we are witnessing the rise of promising methods that can reduce their necessity. We are entering a new era where incredibly realistic in vitro biological models are being developed. In some cases, these models are so accurate that animal usage may not be essential. In the foreseeable future, I anticipate a significant portion of pure research being conducted without relying on animal models.”

At EPFL, research groups are increasingly embracing innovative techniques such as organoids. These multicellular micro-tissues, cultivated from stem cells, replicate the structure and functionality of certain human organs. These methods are revolutionizing basic research, enabling scientists to gain precise insights into the workings of specific mechanisms. However, when it comes to drug development research, where understanding the impact of molecules on a given system is crucial, animal models still play an indispensable role.

Source: Ecole Polytechnique Federale de Lausanne

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