In the earliest stage of life, animals undergo some of their most spectacular physical transformations. Once merely blobs of dividing cells, they begin to rearrange themselves into their more characteristic forms, be they fish, birds or humans. Understanding how cells act together to build tissues has been a fundamental problem in physics and biology.
Now, UC Santa Barbara professor Otger Campàs, who also
holds the Mellichamp Chair in Systems Biology and Bioengineering, and Sangwoo
Kim, a postdoctoral fellow in professor Campàs lab, have approached this
question, with surprising findings.
“When you have many cells physically interacting with
each other, how does the system behave collectively? What is the physical state
of the ensemble?” said Campàs.
Indeed, he explained, embryonic
cellular tissue is a “weird material,” with each cell consuming
chemical energy and using it to apply forces to its neighbors and coordinate
their actions. In-vitro studies with cells in synthetic dishes provide only
part of the picture, he added; by studying cells in their native environment,
the living embryo, they could find out how cells control their collective state
and the phase transitions that emerge from their symphony of pushes and pulls.
In a paper published in Nature Physics, Campàs, Kim and
colleagues report the development of a computational framework that captures
the various interactions between cells and connects them to embryonic tissue
dynamics. Unlike previous simulations, this framework takes into account
several key features relevant to cell interactions, such as spaces between
cells, cell shapes and tension fluctuations where the cells meet.
“To fully understand the physical behavior of
embryonic tissues, all key aspects of embryonic tissues at cellular scales
should be taken into account in the model as emergent tissue properties derives
from interactions at the cellular scale,” said Kim, the lead author of the
study. “There are numerous models to study embryonic tissues, but there is no
general framework that includes those key features, hindering the holistic
understanding of the physical behaviors of embryonic tissues.”
Jiggling Cells
Embryonic tissue, according to the researchers,
behaves physically somewhat like an aqueous foam, a system composed of
individual pockets of air clumped together in a liquid. Think soap suds or beer
froth.
“In the case of foam, its structure and dynamics are
governed by surface tension,” Kim said. Analogous forces are found where
cells come into contact with each other in embryonic tissue, on both the inner
faces of the cell membranes and between cells.
“Effective forces acting on cell-to-cell junctions are
governed by cortical tension and cell-to-cell adhesion,” Kim said, “so the
net force at the cell-to-cell contacts can be modeled as an effective
surface tension.”
However, unlike the more static forces between cells
in typical foams, the forces between cells in embryonic tissue are dynamic.
“Cells in tissues do not generate static forces, but
rather display dynamic pushing and pulling over time,” Campàs explained. “And
we find that it is actually these tension fluctuations that effectively ‘melt’
the tissue into a fluid state.” It is this fluidity of the tissue that allows
cells to reorganize and shape the tissues, he explained.
The researchers put their model to the test by
measuring how forces change over time in embryonic zebrafish, a popular model
organism for those studying vertebrate development. Relying on a technique
developed in the Campàs Lab using tiny magnetic droplets inserted between cells
in embryonic zebrafish, they were able to confirm, by the way the droplet
deformed, the dynamic forces behind the fluid state of the tissue.
Their finding that tension fluctuations are
responsible for the fluidity of tissue during development stands in contrast to
the generally accepted notion that changes in adhesion between cells is the
critical factor that controlled the fluidity of the tissue—if the adhesion
between cells reached a certain high threshold, the tissue would
become fluid.
“But since cell forces and tensions fluctuate in
embryos, it could be that these played an important role in tissue fluidization,”
Campàs said. “So when we ran the simulations and did the experiments, we
realized that actually the jiggling was way more important for the fluidization
than the adhesion.” The fluid state of the tissue is the result of the dynamics
of forces, rather than changes in static cell tension or adhesion.
The findings of this study could have implications in
the field of physics, particularly in the realm of active matter—systems of
many individual units that each consume energy and apply mechanical forces that
collectively exhibit emergent collective behaviors. The study could also inform
studies in biology, in investigations of how changes in individual cell
parameters could control the global state of the tissue such as with embryonic
development or with tumors.
Journal article: https://www.nature.com/articles/s41567-021-01215-1 (paper under paywall)
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