Cells self-organize by following breadcrumb trails in early embryos

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When an embryo starts growing after fertilization, different types of cells begin to form. However, in the early stages of development, some of these cells are initially mixed together. Even before the embryo implants into the lining of the womb, the cells sort themselves into separate regions. Scientists have long wondered: how do cells organize and move to the right places? A new study by the Hiiragi group, published in Nature Cell Biology on February 18, uncovers how embryos achieve precise cell arrangement despite differences in embryo size and shape. The researchers found that specific biological and mechanical signals help cells migrate to their correct locations.

In early mammalian embryos, the inner cell mass is a group of cells that will eventually give rise to the body of the organism. The inner cell mass contains two key cell types: epiblast and primitive endoderm. Epiblast cells eventually develop into the fetus, while primitive endoderm cells contribute to supportive structures like the yolk sac. Initially, these two cell types are mixed in a “salt-and-pepper” pattern. Over time, they sort into separate regions within the embryo. But how does this happen?

Laying the breadcrumbs: cells leave a trail

To answer this question, the researchers used advanced microscopy to follow cells over time in mouse embryos before implantation. They discovered that before sorting is complete, primitive endoderm cells begin depositing molecules into the extracellular matrix, a supportive network of proteins surrounding cells. This creates a gradient—a gradual change in the distribution— of the extracellular matrix that helps guide the movement of cells toward their correct location.

To understand this process more deeply, the research team collaborated with Anna Erzberger and Roman Belousov at EMBL Heidelberg to create computer simulations of how primitive endoderm cells interact with the extracellular matrix. These simulations helped to predict a shift in the distribution of the matrix, and the team confirmed with experiments that molecular signals and mechanical forces work together to organize cells. Scientific discoveries are often the result of teamwork, and this study was no exception. “We are very happy to have collaborated with researchers all over the world,” says first author Prachiti Moghe.

Following the breadcrumb trail

The team found that as the extracellular matrix gradient forms, primitive endoderm cells actively move to their correct location. The cells develop protrusions – small extensions that help them move. They also become polarized, meaning they develop a clear front and back, which helps direct their movement. “We refer to this phenomenon as ‘breadcrumb navigation,’ inspired by how Hansel and Gretel follow a trail of breadcrumbs,” explains Moghe.

Just as Hansel and Gretel use breadcrumbs to find their way through the forest, primitive endoderm cells presumably follow molecular signals in the extracellular matrix gradient to reach their correct destination. This ensures that cells sort themselves efficiently without needing direct coordination with their neighbors.

Size matters

The researchers saw that embryo size affects the outcome of this sorting process. When they generated embryos of different sizes, they found that if an embryo was too large or too small, cells often ended up in the wrong locations. These misplacements could impact later development, potentially leading to developmental disorders. But there will always be natural variation in embryo size, so how does this not normally lead to development issues?

Balance is key

To investigate, the team collaborated with researchers from ASHBi and Kyoto University to compare embryos from different species, including mice and monkeys, and previously published data from humans. They found that the proportion of epiblast and primitive endoderm cells is species-specific and adapted to the embryo’s size and shape. This means that over evolutionary time, embryos may have developed a balance between cell numbers, tissue geometry, and sorting duration to ensure correct cell organization despite natural variation in size.

Defining the extracellular matrix

This study highlights how both mechanical forces and molecular signals shape early development. However, many questions remain. One mystery is how the gradient in the extracellular matrix is generated—do cells actively rearrange or modify the matrix as they move? Understanding these processes could help scientists learn more about developmental disorders and improve techniques for stem cell research and embryo culture. As the team continues their work, they hope to uncover more about how early embryos achieve such precise organization despite natural variability.

Publication

Coupling of cell shape, matrix and tissue dynamics ensures embryonic patterning robustness. Prachiti Moghe, Roman Belousov, Takafumi Ichikawa, Chizuru Iwatani, Tomoyuki Tsukiyama, Anna Erzberger, and Takashi Hiiragi. Nature Cell Biology, 2025.

Takashi Hiiragi is a group leader at the Hubrecht Institute and professor at Graduate School of Medicine and Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University.