To enable tissue renewal, human tissue continually eliminates millions of cells without compromising the integrity, shape, and connectivity of the tissue. The mechanisms involved in maintaining this integrity remain unknown. Scientists at the Pasteur Institute and the CNRS today unveiled a new process that enables eliminated cells to temporarily protect their neighbors from cell death, thereby preserving tissue integrity. This protection mechanism is vital and can result in a temporary loss of connectivity in the event of an interruption. The scientists observed that when the mechanism is deactivated, the simultaneous elimination of several neighboring cells compromises tissue integrity. This lack of integrity could be responsible for chronic inflammation. The results of the research were published in the journal Development cell on June 2, 2021.
Human epithelia are tissues found in several parts of the body (such as the epidermis and inner lining). They consist of layers of contiguous cells that act as a physical and chemical barrier. This role is constantly put to the test both by the external environment and by one’s own renewal. Tissue renewal involves the formation of new cells through cell division and the removal of dead cells. The mechanisms that regulate the ability of epithelia to maintain their integrity in contexts with large numbers of eliminated cells are still poorly understood, although this situation occurs regularly during embryogenesis or the maintenance of adult tissues. For example, more than ten billion cells can be eliminated every day in an adult’s intestine. How are these eliminations orchestrated to maintain the integrity and connectivity of the tissue?
Scientists at the Pasteur Institute and CNRS wanted the mechanisms involved in epithelial integrity and the conditions that can affect epithelial connectivity using Drosophila (or vinegar flies), a laboratory-studied organism with an epithelial architecture similar to that of the People, identify.
With the help of protein-sensitive fluorescent markers, the research team showed that when a cell dies, the EGFR-ERK signaling pathway – a signaling pathway for cell activation that is known for its involvement in regulating cell survival – is temporarily activated in neighboring cells. The scientists observed that activation of the EGFR-ERK signaling pathway protected neighboring cells from cell death for about an hour, thus preventing a group of cells from being eliminated at the same time. “We already knew that this signaling pathway played a key role in regulating cell survival in epithelial tissue, but we were surprised to see such a protective dynamic between cells,” comments Romain Levayer, head of the Cell Death and Epithelial Homeostasis Department at the Pasteur Institute and last Author of the study.
The researchers’ research also shows that inhibiting this protective mechanism has drastic effects on the epithelial tissue: cell elimination occurs randomly and neighboring cells can be eliminated at the same time, resulting in repeated loss of connectivity. Elimination of groups of neighboring cells is never observed in epithelial tissue under normal conditions unless the EGFR-ERK pathway is intentionally inhibited, even when a large number of cells are eliminated.
Using a new optogenetic tool that can control cell death in time and space and bypass the protective mechanism, the scientists confirmed that epithelial integrity was compromised when neighboring cells were eliminated at the same time. “Surprisingly, epithelial tissue reacts very sensitively to the spatial distribution of the secreted cells. Although it can withstand the elimination of large numbers of cells, if only three neighboring cells are eliminated at the same time, epithelial integrity will be compromised, ”explains Léo Valon, scientist in the Department of Cell Death and Epithelial Homeostasis at the Pasteur Institute and lead author of the study.
The scientists’ observations confirm that tissues must develop mechanisms that prevent the elimination of neighboring groups of cells. “These observations are important as they illustrate the incredible ability of biological tissue to organize itself, a property that enables them to withstand stressful conditions. So there is no need for a conductor to orchestrate where and when the cells are to die; everything is based on highly local communication between neighboring cells, ”adds Romain Levayer.
This process seems to have persisted throughout evolution. The same protective mechanism based on local EGFR-ERK activation was independently discovered in human cell lines by Olivier Pertz’s research group at the University of Bern in Switzerland (the results are published in the same journal2). The results of the other study suggest that the protective mechanism is conserved between species hundreds of millions of years apart, suggesting that it is a relatively universal mechanism.
Future research will show whether disruption of this coordination mechanism of cell death and repeated loss of connectivity in epithelial tissue could be a cause of chronic inflammation, a phenomenon responsible for various diseases that are currently among the leading causes of death worldwide.
Video on the distribution of cell death in a Drosophila epithelium:
Video on the activation of the EGFR-ERK signaling pathway in neighboring cells: