Stem Cell Zoo Uncovers Scaling Laws Governing Species-Specific Development

Pregnancy last around nine months in humans, only 20 days in mice, and up to 17 months in rhinoceroses. Even though many mammalian species go through the same phases of embryo development, the rate of development varies greatly between animals.

The development of the vertebrate body axis, the spine, is another example of an event that varies in time between species. A system known as the segmentation clock regulates the creation of the body segments that give rise to the vertebrae and ribs. The segmentation clock is an oscillating set of genes. Each oscillation is responsible for the development of a pair of somites. The frequency of the oscillations varies between species, with humans requiring two to three times longer than mice.

The segmentation clock is a practical system for investigating species differences, and the Ebisuya group has been investigating it for a long time, recently finding that the variations in mouse and human clocks are caused by changes in biochemical reaction speeds.

However, to determine whether this is a general principle of development, researchers needed to diversify the species investigated, which had formerly been limited to humans and mice.

In addition to the mouse and human, scientists from the Ebisuya Group have now reproduced in the lab the segmentation clocks of four novel mammalian species: marmoset, rabbit, cattle, and rhinoceros. This research was carried out in association with research groups from Europe, Japan, and the United States.

What is a Stem Cell Zoo?

A stem cell zoo is a repository of stem cells from several species that can be used to research and compare various developmental events. The collaborative group gathered embryonic stem cells and induced pluripotent stem cells from marmoset, rabbit, cattle, and rhinoceroses, adding to the existing human and mouse libraries.

This diversified species sampling is unprecedented in developmental studies, and it intends to serve as a platform for comparing developmental processes.

We wanted to create a platform of cells from several mammalian species to study why their developmental time is different. We wanted to have as wide a range as possible, so we chose species with body weights spanning from 50 grams to 2 tonnes, gestation lengths from 20 days to 17 months, and three different evolutionary histories or phylogenies: Primates (human and marmoset), Glires (mouse and rabbit) and Ungulates (cattle and rhino).”

Jorge Lázaro, Study First Author and Pre-Doctoral Student, European Molecular Biology Laboratory

The researchers concentrated on the discrepancies in the segmentation clocks of the four novel species. They used experimental techniques to transform embryonic and induced pluripotent stem cells into pre-somitic mesoderm-like cells, which give rise to the spine, ribs, and skeleton muscles.

Our stem cell zoo serves as an ideal platform to investigate the cause of interspecies differences in the segmentation clock period, as well as to determine whether there is any general relationship between segmentation tempo and the characteristics of the organism.”

Miki Ebisuya, Group Leader, European Molecular Biology Laboratory

Miki Ebisuya is also associated with the Cluster of Excellence Physics of Life, TU Dresden.

Correlating the Segmentation Clock

Many biological factors, including gestation length, are known to scale with animal body weight. Larger species have longer gestation periods. As a result, the study speculated that the variations in the segmentation clock could be related to body weight.

Surprisingly, they discovered no association between each species' average body weight and its segmentation clock period. Similarly, there was no correlation between gestation length and segmentation clock period.

Instead, the researchers discovered that the segmentation clock period was strongly connected to the length of embryogenesis. Embryogenesis is the period of time between fertilization and the formation of all organs in an embryo. This could imply that the segmentation clock can be a useful tool for understanding how general embryonic developmental time is established across species.

Moreover, the researchers discovered that the three distinct evolutionary histories—Primates, Glires, and Ungulates—corresponded to slow, fast, and intermediate segmentation clock periods, indicating a link between developmental pace and evolutionary groups.

The Ebisuya group has previously discovered that biochemical reaction speeds correlate with the segmentation clock period. Those investigations, however, were limited to mice and humans.

The team has now expanded the species under investigation and established that the four new mammal exhibit differences in biochemical reaction speeds that correlate very well with the segmentation clock period. This suggests that alterations in biochemical rates could be a general strategy for controlling developmental tempo.

Furthermore, scientists discovered that genes involved in biochemical processes exhibit an expression pattern that coincides with the segmentation clock period, offering clear evidence for a potential molecular mechanism underpinning disparities in developmental speeds between species.

Our aim is to keep adding species in our stem cell zoo. If we want to confirm whether the findings of our research could constitute a universal principle of mammalian development, we need to expand the zoo and include a wider range of species and phylogenies.”

Miki Ebisuya, Group Leader, European Molecular Biology Laboratory

The team focused on the segmentation clock in the current study, which was published in Cell Stem Cell, but the stem cell zoo approach opens the door to studying other biological clocks, such as heart rate or lifespan. The more scientists learn about how biological time works, the more they may be able to harness it. For instance, in the field of organoids, accelerating the time necessary to develop organoids could advance regenerative medicine research.

Lázaro concludes, “Another aspect that I really like about the stem cell zoo is the possibility to learn from different species outside of human and mouse. Many animals have particular features that make them interesting to study, but due to practical or ethical reasons we don’t have access to them in the lab. Features like for example the size of a rhino, or the long neck of giraffes. Who knows, perhaps in our next project we can use stem cells to try to understand how giraffes develop their long neck—and longer somites!”