Tissue Engineering Advances as Insights Grow on How Embryonic Cells Sense Their Mechanical Environment

Researchers from the Physics of Life Cluster of Excellence (PoL) at the Technical University Dresden and the University of California, Santa Barbara, published a study “Mechanics of the cellular microenvironment as probed by cells in vivo during zebrafish presomitic mesoderm differentiation” in Nature Materials that describes how cells sense their mechanical environment as they build tissues during embryogenesis.

The research findings might have important implications for tissue engineering. Potential materials that mimic the foam-like characteristics of the embryonic tissue, as opposed to the widely used synthetic polymer or gel scaffolds, may allow researchers to create more robust and sophisticated synthetic tissues, organs, and implants in the lab, with the appropriate geometries and mechanical characteristics for the desired functions.

“Tissue morphogenesis, homoeostasis and repair require cells to constantly monitor their three-dimensional microenvironment and adapt their behaviors in response to local biochemical and mechanical cues. Yet the mechanical parameters of the cellular microenvironment probed by cells in vivo remain unclear,” write the investigators.

“Here, we report the mechanics of the cellular microenvironment that cells probe in vivo and in situ during zebrafish presomitic mesoderm differentiation. By quantifying both endogenous cell-generated strains and tissue mechanics, we show that individual cells probe the stiffness associated with deformations of the supracellular, foam-like tissue architecture. Stress relaxation leads to a perceived microenvironment stiffness that decreases over time, with cells probing the softest regimen.

“We find that most mechanical parameters, including those probed by cells, vary along the anteroposterior axis as mesodermal progenitors differentiate. These findings expand our understanding of in vivo mechanosensation and might aid the design of advanced scaffolds for tissue engineering applications.”

“We know a lot about how cells sense and respond to mechanical questions in a dish. However, their microenvironment is quite different within an embryo, and we did not know what mechanical cues they perceive in a living tissue,” said Otger Campàs, chair of tissue dynamics and managing director of the PoL.

Helping cells make important decisions

The mechanical cures help cells make important decisions, such as whether or not to divide, move or even differentiate, the differentiation process by which stem cells turn into more specialized cells able to perform specific functions. Previous work revealed that stem cells placed on a synthetic substrate rely heavily on mechanical cues to make decisions:

Cells on surfaces with a stiffness similar to bones became osteoblasts (bone cells), whereas cells on surfaces with a stiffness similar to brain tissue became neurons. The findings advanced the field of tissue engineering as researchers used these mechanical cues to create synthetic scaffolds to coax stem cells to develop into desired outcomes. These scaffolds are used today in a variety of biomedical applications.

However, a dish is not the cell’s natural habitat. While building an organism, cells are not in contact with synthetic scaffolds in a flat dish, but rather with complex living materials in three dimensions.

Over the last decade, Campàs’ research group uncovered the mechanical cues that guide cells in the complex tissues of an embryo. Using a technique developed in his lab, the researchers could probe the living tissue in a similar way as cells do and find out what mechanical structures the cells make sense.

“We first studied how cells mechanically test their micro-environment as they differentiate and build the body axis of a vertebrate, as they differentiate,” Campàs explained. “Cells used different protrusions to push and pull on their environment. So we quantified how fast and strong they were pushing.”

Using a ferromagnetic oil droplet that they inserted between developing cells and subjecting it to a controlled magnetic field, they were able to mimic these tiny forces and measure the mechanical response of the cells’ surroundings.

Critical to these embryonic cells’ actions is their collective physical state, which Campàs and his research group described in a previous paper to be that of an active foam, similar in consistency to soap suds or beer froth, with cells clumped together by cell adhesion and tugging each other. What the cells are mechanically probing, Campàs and team found out, is the collective state of this “living foam”—how stiff it is and how confined the assembly is.

“And right at the moment that cells differentiate and decide to change their fate, there is a change in the material properties of the tissue that they perceive,” he continued, adding that at the moment the cells within the tissue decide on their fate, the tissue falls its stiffness.

What’s not yet proven in this study is the complex question of whether, and if so, how the change in the stiffness in the embryonic environment drives the change in the cell state.

“There is an interplay between the mechanical characteristics of the structures that cells collectively build, such as tissues or organs, and the decisions they make individually, as these depend on the mechanics cues that cells sense in the tissue. This interplay is at the core of how nature builds organisms,” noted Campàs.

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