A protein best known for helping cells and tissues stay connected has revealed an unexpected secondary role that could change how scientists view tissue maintenance and immune defense. Researchers have discovered that the E-cadherin complex—traditionally understood as the vital molecular "glue" that binds epithelial cells together—also plays a critical part in helping these cells engulf nearby dead material.
This unexpected biological cleanup operation, detailed in a recent study published in Nature Communications, could carry profound implications for understanding chronic inflammation and various degenerative conditions. Debris left behind by dying cells is a major contributor to inflammatory responses within the human body. By understanding the precise physiological mechanisms by which tissues remove this cellular waste, scientists hope to uncover fresh clues about what happens when this delicate cleanup process fails.
The research was led by a team under the direction of ICREA Research Professor Verena Ruprecht, with joint first authors Hanna-Maria Häkkinen, Marta Batet Palau, and Laura F. Bianchi. Their work sheds light on how fundamental cellular structures multitask to preserve tissue integrity and manage waste without compromising vital physical barriers.
Cellular Glue Takes on a Cleanup Role
To understand this newly discovered phenomenon, the researchers examined epithelial tissues in living zebrafish and mouse embryos. Epithelial cells form continuous, tightly sealed layers that line major organs and structures throughout the body, including the skin, gut, and airways. These cells give tissues the structural strength they need to remain intact by connecting directly to E-cadherin molecules found on the surfaces of neighboring cells.
During their investigations, Ruprecht and her team observed that the exact same molecular machinery utilized for cell-to-cell adhesion also gathers precisely at the location where a dying cell comes into contact with the tissue. This surprising convergence raised immediate questions regarding how the machinery operates in these distinct contexts.
Specifically, the researchers wanted to determine whether E-cadherin and its associated partner proteins were physically attaching to the dying cell in the same manner they normally link neighboring epithelial cells. To test this hypothesis, they designed a pair of targeted experiments.
First, the team presented the epithelial tissue with dying cells that had been intentionally stripped of E-cadherin. Surprisingly, the tissue removed these deficient cells just as effectively as it removed normal dying cells. Next, the researchers introduced synthetic fat droplets that contained no proteins at all, but were engineered to carry a specific molecular signal normally displayed on the surface of dying cells. To the team’s astonishment, the epithelial cells engulfed those protein-free droplets as well, proving that the cellular machinery was responding to general clearance cues rather than engaging in traditional cell-to-cell binding.
"We were intrigued to find out that epithelial cells repurpose their molecular adhesion machinery—the ‘glue’ that normally holds them together—to engulf dying cells," says Verena Ruprecht, senior author of the study.
How Cells Eat Without Breaking the Barrier
Engulfing foreign or dying material that is roughly the size of another living cell presents a severe mechanical problem for biological systems. Epithelial cells are packed tightly together into robust barriers that frequently need to remain completely sealed, even while individual cells undergo dramatic structural shifts to remove debris.
Through advanced live imaging, the researchers were able to observe exactly how epithelial cells accomplish this delicate balancing act. They discovered that the upper and lower surfaces of the same epithelial cell can behave in completely different ways. While the lower surface stretches, bends, and actively maneuvers around the dead cell, the opposite, upper surface remains relatively unchanged.
That upper surface, which typically faces the outside environment or an open space such as the interior lumen of an organ, continues to maintain the structural integrity of the tissue barrier. Measurements taken before, during, and after the engulfment process demonstrated that the total area of the upper surface changed very little. In stark contrast, the lower surface underwent substantial and complex deformation during the "eating" process.
Ruprecht compares this remarkable cellular behavior to a row of traditional dancers standing side by side with their arms firmly linked. While their upper bodies remain steady and composed, their feet perform increasingly complicated movements whenever a dying cell appears. "It’s the same dancer with a different choreography," she notes.
A Molecular Rope and Brake
To dig deeper into the mechanics driving this process, the researchers analyzed the specific components that allow epithelial cells to perform this cleanup operation.
They found that one particular protein within the E-cadherin complex acts much like a physical rope. This protein connects the broader molecular assembly directly to the cell’s internal skeleton, or cytoskeleton, allowing mechanical force to be transmitted across the surface of the material being engulfed. When cells were experimentally modified to lack this tethering protein—or when they lacked the specific structural region required to attach it to the cytoskeleton—they completely lost the ability to swallow dead cells.
Another component of the complex behaved more like a regulatory brake on the cell’s internal contractile machinery. Surprisingly, when the researchers removed this biological brake, it did not make the cleanup process faster or more efficient. Instead, the cell became excessively stiff, ultimately losing its ability to properly remove the dying material altogether. This revealed that successful engulfment requires a precise balance of both driving forces and mechanical restraint.
The Same Mechanism Appears in Mammals
Following their initial discoveries in zebrafish, the research team investigated whether this cleanup process extends to mammalian systems.
In experiments utilizing early mouse embryos, blocking E-cadherin caused dying cells to remain uncleared, mirroring the exact results previously observed in zebrafish. This cross-species consistency suggests that the mechanism is broadly shared among vertebrates, pointing to an evolutionarily conserved process for managing cellular waste.
This new work builds directly upon earlier research from Ruprecht’s laboratory, which demonstrated that embryos can use epithelial tissues to cooperatively remove dying cells. That coordinated behavior functions as an early, primitive form of innate immune defense long before the developing organism has a fully mature immune system.
Embryos serve as particularly valuable models for studying these dynamic events because they are optically transparent. This transparency allows researchers to observe living cells and tissues directly at a level of microscopic detail that cannot currently be achieved inside the dense, complex tissues of an adult human body.
Looking Ahead to Adult Tissues and Human Health
Despite these significant breakthroughs, an important question remains unanswered: researchers do not yet know whether this exact E-cadherin-dependent mechanism operates in adult zebrafish, adult mice, or any type of human tissue.
Nevertheless, there are compelling reasons to believe it does. Epithelial tissues in adult organisms are already well-documented to remove dying cells in critical areas, including the retina, colon, airways, and mammary gland. Furthermore, E-cadherin is abundantly expressed throughout epithelial tissues across the human body, and its molecular structure has remained remarkably well-preserved across different species throughout evolutionary history. These shared characteristics make it a strong candidate for a universally utilized cellular cleanup mechanism.
The potential medical significance of the finding stems directly from what happens when dead cells are not removed efficiently. If dying cells linger in tissues for too long, they eventually rupture and release their intracellular contents into the surrounding microenvironment, directly contributing to chronic inflammation and tissue damage.
The findings suggest that successful tissue clearance depends on much more than a cell simply receiving the correct chemical signal to engulf apoptotic debris. Cells must also possess the physical capacity to change shape, generate and withstand mechanical force, and wrap around dead material without compromising themselves or the integrity of the surrounding tissue barrier.
"Studying the mechanisms of how dying cells can be removed efficiently from tissues is of very high relevance to human health," concludes Ruprecht.
The study was led by joint first authors Hanna-Maria Häkkinen, Marta Batet Palau, and Laura F. Bianchi, under the supervision of Verena Ruprecht. Financial support for the research was provided by the Spanish Ministry of Science and Innovation, the Human Frontier Science Program, the European Union’s Horizon Europe program, and the "la Caixa" Foundation, with additional assistance from the European Social Fund. The project also utilized the advanced resources of the CRG Core Facilities for Advanced Light Microscopy, Tissue Engineering, and Protein Technologies.