How communication between cells affects the development of multicellular tissue

Using a combination of computer modeling and experimental techniques, a research team has developed new insights into the impact of intercellular communication on the differentiation of an embryonic stem cell colony over time.

By providing new insights into the role of cell-to-cell communication, the research could lead to a better understanding of how multicellular organoids are formed from colonies of independent cells. This information could lead to new methods of controlling the development of multicellular constructs, which could have applications in regenerative medicine, in pharmaceutical tests and in other areas of research.

The research results from the collaboration between the Georgia Institute of Technology and the Gladstone Institutes and was reported on October 5 in the journal Nature Communications. Emerging behaviors at the National Science Foundation (NSF) Center for Integrated Cellular Systems Science and Technology (EBICS) supported the research.

"The goal is to control a cell system like this one to direct tissues to different phenotypes, to develop different complex mixtures and to self-assemble and emerge into very complex structures," said Melissa Kemp, associate professor at Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "For developing tissues that could be used as surrogates for drug screening or as potential implants for therapeutic purposes, we need to know how to control and direct them properly."

Scientists believe that the structuring of stem cell differentiation affects the types of cells that will emerge from the differentiation process.

Despite the importance of local cell-to-cell interactions in evolving multicellular systems, little is known about how the global system regulates its morphological processes. To learn more about this, Chad Glen, his lead author, has studied how communication between adjacent cells affects the fate of these cells. Beyond understanding this communication, Glen discovered a potential mechanism to "curb" the rate of differentiation without affecting the overall pattern of the resulting multicellular tissue.

"The amount of coordination between tightly coupled cells gives us an idea of ​​how they work as a group," said Todd McDevitt, Senior Research Fellow at Gladstone Institutes and Professor of Bioengineering and Therapeutic Sciences at the University. from California to San Francisco. . "This reflects the behavior of a team in relation to individuals, who are actually coordinating their activities in a fast way.This study shows how quickly certain important cell behaviors are mediated by junction communication."

Glen, a recent doctoral graduate from Georgia Tech, the project began with the study of communication between pairs of adjacent cells, with pores allowing the entry of small molecules. By introducing a signaling molecule into a colony containing hundreds of these homogenous mouse stem cells, the researchers observed that differentiation began with a change in a single cell. This cell triggered a pattern of differentiation that went through the cells and eventually led to changes throughout the colony.

On a larger scale and in three dimensions, such changes lead to the development of bodily organs. Understanding how this happens – and how it could be controlled – could be essential to direct this transition of individual cells.

Based on experimental observations, Glen developed a model of the process, which allowed researchers to study the impact of a series of interdependent variables that would have been impossible to study experimentally. Modeling several hundred individual cells led to specific predictions that the researchers then experimentally tested.

To understand and measure the cellular communication process, the researchers used a fluorescent dye to indicate when signaling molecules were passed from one cell to another. They then used a laser to whiten the dye from a single cell. Measuring the time required to replace the dye shows the permeability of the cell membrane and the degree of communication of the cell with its neighbors.

"If you zap a cell and it becomes green again, you know that there is a lot of fluidity and crosstalk between the cell membranes," Kemp explained. "If you block a cell and it stays dark, the cell is effectively isolated and does not communicate with its neighbors."

By partially blocking communication between cells and disrupting communications, the researchers slowed the differentiation process, but did not change the pattern. "We have managed to change the behavior of cells to slow things down – effectively curbing the process – while preserving spatial information," Kemp said. "The cells that were at 48 hours in the process could look like 24-hour cells."

The combination of computer modeling and experience allowed the research team to find answers that no single technique could have provided, noted McDevitt.

"With modeling, you can study a much larger set of conditions and parameters than we could do experimentally," he said. "The model could make predictions that we could go back and study experimentally to see how these conditions actually affect behaviors." The behaviors we measured experimentally matched those predicted by the computer and confirmed that we had a model robust."

McDevitt and Kemp have been studying this embryonic stem cell system for several years and the new study brings them closer to a more complete understanding of the complex system.

"We have demonstrated in a series of articles over the last six years that the complexity of this system can be modeled," he said. "This document represents one more step towards the more important goal of integrating information about this system.With each of these steps, we are much closer to a bigger jump in potential control." of these systems. "

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More information:
Chad M. Glen et al., Dynamic intercellular transport modulates the spatial pattern of differentiation during early neuronal engagement. Nature Communications (2018). DOI: 10.1038 / s41467-018-06693-1