Endoplasmic reticulum controls cell movement to repair tissue gaps

The body's cells change their shape to close gaps such as wounds – with part of the cell flexing depending on the curve of the gap and the organization of cell-internal structures, a new study reveals.

Epithelial cells line the body's surfaces inside and out - forming a barrier to protect against physical damage, pathogens, and dehydration. They play key roles in absorbing nutrients and removing waste products, as well as producing substances such as enzymes and hormones.

Scientists have discovered that these cells' endoplasmic reticulum (ER) changes its shape in different ways. When the gap curves outward (convex), the ER forms tube-like shapes, but when the gap curves inward (concave) it forms flat sheet-like shapes.

The researchers found that pushing forces at outward-curving edges and pulling forces at inward-curving edges change the shape of the ER through different mechanisms.

When a gap has convex edges, the cells use a crawling movement with broad, flat extensions, but in the case of concave edges there is a 'purse-string' movement, where the cells contract to pull the edges together.

Publishing their findings today (18 Aug) in Nature Cell Biology, researchers from the UK and India note that the ER's ability to reorganize in response to edge curvature and determine the mode of epithelial migration highlights its crucial role in cellular behavior.

Scientists used specialised techniques to create tiny gaps in cell layers and used advanced imaging and mathematical models to understand how the ER changes shape and helps epithelial cells move.

Dr. Simran Rawal from the Tata Institute of Fundamental Research Hyderabad, who performed most of the experiments, commented: "Wound healing is an important response to injury. Our study opens new avenues for exploring the mechanisms underlying epithelial gap closure and their broader implications for health and disease by identifying a new role of the ER in this process."

Dr. Pradeep Keshavanarayana, who developed the mathematical model when he was a Research Fellow at the University of Birmingham, remarked: "The ER's role in cell movement is not just a fascinating scientific discovery but also a potential game-changer for various medical treatments and therapies. Using mathematical models to understand how cells repair themselves may lead to better treatments for wounds, new methods for regenerating damaged tissues, or an improved grasp of how cancer cells spread - leading to new strategies to prevent or slow down metastasis."

This project was a great example of a fruitful interdisciplinary collaboration. We previously studied endothelial monolayers, which are the cells that line blood vessels, and investigated how mechanical and geometrical features regulate gaps in the monolayer that can cause leakiness.

The experiments showed a novel, unexpected link between organelle and cell shape and monolayer behavior. The combination of these beautiful experiments by Simran and collaborators with the mathematical model developed by Pradeep led to the identification of a new, organelle-mediated mechanism of sensing mechanics and geometry."

Fabian Spill, Corresponding Author, Professor, University of Birmingham

Professor Tamal Das, corresponding author from the Tata Institute, added: "This study started with the discovery made by Simran, who observed the ER's central role in mechanotransduction - the process by which cells convert mechanical stimuli from their environment into biochemical signals.

"Mechanotransduction is fundamental to several physiological functions, including touch, hearing, and balance, and has been studied in the context of collective cell migration. Our collaboration shaped the theoretical framework and deepened our understanding of the underlying mechanisms. Together, our experiments and modelling reveal a novel role for the ER in this process."