How Cells Sense Shape to Heal Wounds — The Role of Endoplasmic Reticulum
The endoplasmic reticulumun has an expected role in orchestrating cell migration during tissue repair. At convex edges, where lamellipodial crawling occurs, the endoplasmic reticulum reorganised into thin tubules. At concave edges, where cells contract to close the gap, the endoplasmic reticulum formed sheet-like domains that worked with actin bundles
Our bodies are constantly challenged by changes in their environment, and when tissues are damaged, nearby cells must move in quickly to close the gap and restore protection. Cells do not rely on a single strategy for this task, the way they migrate depends on the shape of the wound. At outward-curving (convex) edges, they extend flat protrusions called lamellipodia to crawl forward, while at inward-curving (concave) edges, they assemble a contractile actin ring that pulls the tissue together like a purse string. What has remained unclear is how cells detect these geometric cues and decide between these two modes of migration.
Deciphering the role of endoplasmic reticulum
Our study, now published in Nature Cell Biology, we mapped the distribution of cytoskeletal proteins and organelles in cells responding to different wound shapes. This revealed the endoplasmic reticulum as a key organelle in sensing curvature. The endoplasmic reticulum, best known for producing proteins and lipids, turned out to be highly adaptable in its structure. At convex edges, where lamellipodial crawling occurs, the endoplasmic reticulum reorganised into thin tubules. At concave edges, where cells contract to close the gap, the endoplasmic reticulum formed sheet-like domains that worked with actin bundles. By experimentally altering the endoplasmic reticulum morphology using proteins that control its shape, we found that forcing cells to form more endoplasmic reticulum tubules pushed them toward lamellipodial migration even at concave edges. These results point to the endoplasmic reticulum morphology as a decisive factor in determining how cells move.
Minimising strain energy
To understand why endoplasmic reticulum shape matters in this context, we developed a mathematical model with colleagues Dr. Pradeep Keshavanarayana and Dr. Fabian Spill at the University of Birmingham. The model showed that cells minimise strain energy when endoplasmic reticulum is tubular at convex edges and sheet-like at concave edges, offering a physical explanation for this reorganisation.
Together, these findings highlight the endoplasmic reticulum as more than just a factory for cellular components. It acts as a sensor and regulator, translating curvature into structural changes that shape collective cell migration. This redefines how we think about organelles: they are not limited to internal housekeeping but can directly influence tissue-level behaviours.
Implications of the study
The implications of this work extend beyond wound healing. Collective migration drives many biological processes, from embryonic development to cancer invasion. Knowing that the endoplasmic reticulum can bias migration strategies provides a new entry point for studying these events and suggests that targeting endoplasmic reticulum dynamics may help guide tissue repair or limit invasive growth in disease.
In summary, our study reveals an unexpected role for the endoplasmic reticulum in orchestrating cell migration during tissue repair. It shows how cells integrate physical cues with internal organelle remodelling to maintain tissue integrity.
