Epithelial tissues constantly engage with their surroundings. To function effectively, they must maintain a delicate balance (homeostasis) and carefully regulate their cell populations. This regulation occurs through cell extrusion programs, which act as a checkpoint system to remove unwanted or harmful cells. Researchers from the Max-Planck-Zentrum für Physik und Medizin (MPZPM), Institut Jacques Monod (CNRS, UP Cité, France), and the Niels Bohr Institute (Denmark) have recently shown how physical signals can influence the fate of cells being extruded, determining whether they live or die. Their findings, published in “Nature Physics“, may open new avenues for understanding tissue characteristics in both healthy and diseased states.
Epithelial cells are dynamic and must frequently renew themselves. As a result, the process of removing cells from a tissue, known as apoptotic extrusion, occurs on a regular basis and is crucial for maintaining homeostasis. In addition to supporting tissue health, cell extrusion significantly contributes to changes in tissue shape and the advancement of tumors. Thus, mechanisms of extrusion can crucially influence cell outcomes, as pushing out either dead or alive cells can lead to dramatically different biological effects. This is especially vital during developmental stages when tissues or organs are being formed and also has a notable impact on disease progression, such as in cancer. Even though cell extrusion is known to be impactful in both development and aging, as well as in cancer advancement, the factors that dictate the fate of an extruded cell have not been well understood until now.
Mechanical intercellular forces influence the fate of extruding cells
Cells in epithelial layers exert forces on their neighboring cells, which can initiate cell detachment and elimination. Although removing dead cells is key in disposing of unsuitable or unnecessary cells, the extrusion of live cells plays a significant role in development and is often associated with disease responses. A research team led by Prof. Benoît Ladoux at MPZPM, in collaboration with Prof. Amin Doostmohammadi from the Niels Bohr Institute and Dr. René-Marc Mège from the Institut Jacques Monod, propose that the mechanical forces at play among epithelial cells affect the extrusion process and ultimately determine the fate of these cells.
The researchers demonstrated that the intensity and duration of the forces applied affect whether cells extruded are alive or dead. These physical cues are influenced by the strength of intercellular connections, particularly the E-cadherin junctions. Furthermore, they found that cells can be extruded either apically or basally into the tissue, contingent on the mechanical intercellular forces involved. Notably, living cells were more often found to be extruded toward the basal side.
Teams led by Ladoux, Mège, and Doostmohammadi merged physical modeling of three-dimensional cell structures with experiments using cells expressing different levels of certain proteins. These proteins, which connect cells and act as mechano-sensors (specifically E-cadherin based), play a role in regulating cell-to-cell interactions. Their collaborative work, involving Dr. Philippe Chavrier’s team from the Curie Institute, revealed that changes in how force is transmitted through cell junctions (adhesion junctions) can modify apoptotic cell death during the extrusion process. Moreover, the altered force transmission led to a shift in the extrusion direction from apical to basal, further impacting the fate of the extruded cells.
“Our research highlights that distinct modes of cell extrusion are linked to changes in the creation, exertion, and transfer of mechanical forces within the tissue, leading to modifications at the genetic and protein levels,” says Ladoux. “Therefore, the transfer of intercellular forces managed by cell-to-cell communication is essential for cell extrusion mechanisms, which could have implications during morphogenesis and the invasion of cancer cells.”
“Our findings also emphasize the importance of force transmission regulated by how epithelial tissues interact through adherens junctions, providing insights into the role of these junctions in various cancer tissues,” add Dr. Lakshmi Balasubramaniam and Dr. Siavash Monfared, co-first authors of the study.
