A protein best known for helping cells and tissues stay connected has another unexpected role. Researchers have found that it also helps epithelial cells, which form continuous sealed layers throughout the body, engulf nearby dead cells.
The discovery could have implications for chronic inflammation. Debris from dying cells is an important contributor to inflammatory responses, so understanding how tissues remove that material may reveal new clues about what happens when the cleanup process fails.
The study, published in Nature Communicationsfocuses on the E-cadherin complex. This molecular system includes E-cadherin along with three additional proteins. Together, they connect the epithelial cells that line areas such as the skin, intestine and airways, giving tissues the structural strength they need to remain intact. In these tissues, each cell connects to E-cadherin molecules from neighboring cells.
Cell glue takes on a cleaning function
A team led by Verena Ruprecht examined epithelial tissues in live zebrafish and mouse embryos. They discovered that the same molecular machinery also gathers at the exact spot where a dying cell comes into contact with tissue.
The researchers wanted to know if E-cadherin and its partners were binding to the dying cell in the same way they normally attached to neighboring epithelial cells. To test that possibility, they conducted two experiments.
First, they presented the tissue with dying cells that had been stripped of E-cadherin. The epithelial tissue removed these cells as effectively as normal dying cells. Next, the team introduced fat droplets that contained no protein but carried a signal normally displayed on the surface of dying cells. Epithelial cells also engulfed those droplets.
“We were intrigued to discover that epithelial cells reuse their molecular adhesion machinery (the ‘glue’ that normally holds them together) to phagocytose dying cells,” says ICREA Research Professor Verena Ruprecht, senior author of the study.
How cells eat without breaking the barrier
Swallowing something about the size of another cell presents a difficult mechanical problem. Epithelial cells are packed into barriers that often need to remain sealed, even as individual cells remodel to remove debris.
Live footage revealed how they achieve this. The upper and lower surfaces of the same epithelial cell can behave differently from each other. The bottom surface stretches and bends around the dead cell, while the opposite side remains relatively unchanged.
That upper surface, which may face the outside environment or an open space such as the interior of a lumen, continues to maintain the tissue barrier. Measurements taken before, during and after the dive showed that the top surface area changed very little. In contrast, the bottom surface underwent substantial deformation during the “eating” process.
Ruprecht compares the behavior to a line of dancers standing with their arms linked. His upper body remains steady while his feet perform increasingly complicated movements as a dying cell appears. “It’s the same dancer with different choreography,” he says.
A molecular rope and a brake
The researchers also examined the mechanics that allow cells to do this cleaning.
A protein in the E-cadherin complex acted much like a rope. It connected the molecular assembly to the cell’s internal skeleton, allowing force to be transmitted across the surface of the material being engulfed. When cells lacked this binding protein, or lacked the specific region that attaches it to the skeleton, they could no longer swallow dead cells.
Another component behaved more like a brake on the cell’s contractile machinery. Surprisingly, removing this brake did not make the cleaning process more effective. Instead, the cell became too rigid and lost its ability to properly remove dying cells.
The same mechanism appears in mammals
Next, the team investigated whether the process extends beyond zebrafish.
In early mouse embryos, blocking E-cadherin caused dying cells to remain unremoved. This was consistent with results observed in zebrafish and suggests that the mechanism is shared among vertebrates.
The new work builds on Ruprecht’s earlier research showing that embryos can use epithelial tissues to cooperatively remove dying cells. That behavior represents a form of early innate immune defense.
Embryos are particularly useful for studying these events because they are transparent. Researchers can observe living cells and tissues directly with a level of detail that currently cannot be achieved within the human body.
Could the same process work in adult tissues?
An important question remains unanswered. Researchers do not yet know whether this same E-cadherin-dependent mechanism operates in adult zebrafish or mice, or in any type of human tissue.
There are reasons to think that this could be the case. Epithelial tissues in adults are already known to remove dying cells in places such as the retina, colon, respiratory tract, and mammary gland. E-cadherin is also found in all epithelial tissues of the body and its structure has remained remarkably similar between species. Those characteristics make it a strong candidate for a more widely used cleaning mechanism.
The potential medical importance comes from what can happen when dead cells are not removed efficiently. Dying cells that remain in tissues can eventually rupture and release their contents, contributing to chronic inflammation.
The findings suggest that successful cleanup depends on more than just receiving the right chemical signal to absorb apoptotic waste. Cells must also be physically capable of changing shape, applying force, and enveloping dead material without compromising themselves or surrounding tissue.
“The study of the mechanisms by which dying cells can be effectively removed from tissues is of great importance for human health,” concludes Ruprecht.
The work was led by joint first authors Hanna-Maria Häkkinen, Marta Batet Palau and Laura F. Bianchi and supervised by Verena Ruprecht. It has been financed by the Ministry of Science and Innovation of Spain, the Human Frontier Scientific Program, the Horizon Europe program of the European Union and the “la Caixa” Foundation, with additional support from the European Social Fund. It made use of the CRG’s core facilities for advanced optical microscopy, tissue engineering and protein technologies.