Northwestern Medicine scientists have discovered a previously unknown process used by epithelial cells to alleviate epithelial tissue crowding and avoid cell damage and loss, according to a recent study published in Nature Communications.
“This is a new mechanism for dealing with tissue crowding that doesn’t involve cell loss, which is destructive and costly to the tissue,” said Brian Mitchell, PhD, associate professor of Cell and Developmental Biology and senior author of the study.
Enzo Bresteau, PhD, a postdoctoral fellow in the Mitchell laboratory, was the lead author of the study.
“I would like to highlight the significant contributions to this study from Dr. Bresteau, whose creativity and perseverance drove this work,” Mitchell said.
Epithelial tissue covers all external and internal surfaces in the body and makes up the lining of all organs. These tissues, which are made of epithelial cells, serve as a protective barrier between organs and withstand different environmental stressors and tissue remodeling.
Epithelial tissue crowding, or the accumulation of too many epithelial cells in a single tissue, can result in cell extrusion, an irreversible process in which the tissue gets rid of cells to help maintain proper balance.
Previous work from Mitchell’s laboratory had revealed that during cell extrusion, previously unknown circular structures containing the protein actin, which supports the shape and structure of eukaryotic cells, were involved.
In the current study, the investigators further studied these actin circular structures in frog embryos and discovered that they play a key role in macropinocytosis, a process in which the cell essentially engulfs surrounding nutrients to survive.
Macropinocytosis is a phenomenon that has been previously observed in cancer, in which cancer cells proliferate so rapidly that they need to acquire nutrients through the process in order to survive.
In epithelial cells, Mitchell’s team discovered that macropinocytosis occurs on the apical surface, or the outermost surface of the cell, which actually causes the apical cell surface to become smaller.
“Macropinocytosis was shrinking the apical surface because it was using all this membrane to pull in the extracellular material. We thought that maybe this was regulated by the same thing that was regulating cell extrusion, which is this mechanosensory activation that is driven by tissue crowding,” said Mitchell, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Additionally, the scientists found that pharmacologically inhibiting macropinocytosis increased cell extrusion in the epithelial cells, highlighting a novel role for macropinocytosis as an additional and less-destructive mechanism for cells to regulate tissue crowding and remodeling.
“As this tissue gets crowded, these events happen periodically to stop them from needing to go through this cell extrusion process. Both of these processes can solve the problem, but cell extrusion is more costly and non-reversible,” Mitchell said.
Mitchell said that in future investigations, he and his team will aim to better understand the molecular mechanisms that regulate macropinocytosis and to study the process in different organoid models.
“One thing we’d like to do is to find other tissues where this is happening to understand how universal this process is,” Mitchell said.
Co-authors include Eve Suva, a student in the Driskill Graduate Program in Life Sciences (DGP); Constadina Arvanitis, PhD, research associate professor of Cell and Developmental Biology; and Farida Korobova, PhD, research assistant professor of Cell and Developmental Biology.
Additional co-authors include Oliver Jenson, PhD, and Sarah Woolner, PhD, at the University of Manchester.
This work was supported by the National Institute of General Medical Sciences (R01GM089970), Wellcome Trust (225408/Z/22/Z), the Biotechnology and Biological Sciences Research Council (BB/T001984/1) and The Leverhulme Trust (RPG-2021-394).
