Dying cells are usually removed from epithelial layers to stop harmful substances and pathogens from entering the body, although the exact process behind this mechanism is not fully understood. A recent study has identified a calcium-dependent mechanism crucial for surrounding cells to eject a dying neighbor. Their discoveries clarify multiple aspects of this complex process, which may improve our understanding of epithelial diseases like atopic dermatitis and inflammatory bowel disease.
A group of researchers from Kyushu University in Japan has found a calcium-driven mechanism that significantly contributes to the disposal of dead cells, offering insight into how our bodies defend against injuries and illnesses. Their study, published in Current Biology on September 23, 2024, demonstrated that levels of calcium ions are vital for effectively removing dead or apoptotic cells from epithelial tissues (the layers of cells that line body surfaces), utilizing specially modified epithelial tissue cultures, molecular markers, and advanced imaging technologies.
Epithelial cells form protective sheets covering the surfaces of our bodies, including the skin and internal organs. When these cells suffer damage and die (a process called apoptosis), adjacent cells quickly cooperate to expel them and seal off any openings that could allow harmful substances to enter and cause infections or inflammation. Although this intricate process is crucial for sustaining a healthy epithelial barrier, the exact mechanisms involved have not been completely understood—until now.
This study, led by Professor Junichi Ikenouchi and his team members, Dr. Kenji Matsuzawa and Mr. Yuma Cho (the primary author), included collaboration with researchers from the University of Tokyo and Health Sciences University of Hokkaido in Japan.
To get started, the researchers induced apoptosis in specific epithelial cells using a focused laser and monitored the response of surrounding cells. They modified nearby cells to express special calcium ion probes called GCaMP6, enabling them to visualize real-time fluctuations in calcium levels. Remarkably, they discovered that the cells neighboring the dying cell exhibited a notable surge in calcium levels, particularly in areas of the membrane adjacent to the apoptotic cell. The researchers coined this interesting occurrence the “calcium response in effectors of apical extrusion (CaRE).”
To further investigate this newly identified mechanism, the team assessed the function of IP3 receptors, which are proteins in cells that help regulate calcium ion concentrations. They discovered that blocking the activity of IP3 receptors or removing their associated genes entirely halted the expulsion of dying cells. Additional investigations using advanced electron microscopy indicated that a specific group of IP3 receptors, especially those located near desmosomes, is crucial for the CaRE process.
Desmosomes are adhesion structures that create strong connections between cells, serving as the “buttons” that keep them together. They hold particular significance in tissues like skin and organ linings, ensuring structural integrity and proper functioning. By ensuring close adherence among neighboring cells, desmosomes play an essential role in maintaining the organization and stability of body tissues. The team found that activating IP3 receptors near desmosomes is vital for initiating the contraction of a group of proteins known as the actomyosin complex, which helps cells alter their shape and move as a means of facilitating the removal of dying cells. “Our research reveals a new function of IP3 receptors in desmosomes, which were previously regarded solely as components for mechanical connections between epithelial cells,” notes Ikenouchi.
As this research was conducted on cultured cells, the team emphasizes that further exploration of the CaRE mechanism is necessary to verify whether this process also occurs in living organisms, if it varies across different organ tissues, and whether other elements might play a role.
In summary, this study enhances our knowledge of how our bodies preserve a healthy epithelium—something we often take for granted. “Our findings offer valuable insights into understanding diseases stemming from epithelial barrier dysfunction, such as atopic dermatitis and inflammatory bowel disease, and may aid in the development of new preventive strategies and treatments for chronic inflammation,” Ikenouchi concludes.
