New research from the University of Utah John and Marcia Price College of Engineering identifies a key mechanism that determines how cells spread and organize their internal structure. The study shows that a cell’s behavior depends on how long the cell receptors known as integrins stay attached to the extracellular matrix. Long-lasting attachments lead to organized internal structures, generating strong pushing forces that allow cells to spread. Short-lived attachments lead to disorganized internal structures and weaker force generation.
The research, published in Communications Materials, was led by Tamara C. Bidone, assistant professor in the Department of Biomedical Engineering and member of the Scientific Computing and Imaging Institute (SCI), along with Remi Sondaz, a fourth-year PhD candidate in biomedical engineering and Keith Carney, a senior research engineer specializing in physics-based modeling and instrumentation at SCI. They collaborated with Jungkyu (Jay) Kim, associate professor in the Department of Mechanical Engineering, as well as oncology researchers at the University of Lund, Sweden.
Using a combination of computational modeling and high-resolution imaging, the researchers demonstrate that simply keeping integrins attached for longer allows the actin cytoskeleton to reorganize and enables cells to spread, even on soft materials where they normally would not.
Cells are constantly interacting with the material around them. When that material is stiff, cells tend to flatten and spread themselves out. When it is soft, cells usually stay round. While this behavior has been known for years, scientists have not fully understood how cells sense these differences and reorganize their internal structure in response.
Receptors known as integrins play a central role in how cells sense and respond to their surroundings. These proteins span the cell membrane, linking the extracellular matrix outside the cell to the actin cytoskeleton inside it. Actin filaments form the cell’s internal support system and generate the forces that push the cell membrane outward during spreading.
Actin can organize in different ways. In some cases, it forms branched networks that push in many directions and generate weaker force. In other cases, actin aligns into bundled filaments that push in a single direction, producing stronger, more focused forces that help cells become polarized.
“What we wanted to understand was what actually determines that transition,” says Bidone. “We know cells behave differently on soft and stiff substrates, but the question is what physical mechanisms inside the system is responsible for reorganizing the cytoskeleton.”
To study this, the team developed a computational model that simulates how actin grows, branches and generates force as cells spread, as well as how integrins attach and detach to the external environment. This approach allowed the researchers to focus specifically on how long integrin bonds last, without changing other chemical signals in the cell.
“I enjoyed applying my physics background and modeling expertise to a new biomechanical problem,” Carney says. “Bringing a physics-based modeling perspective to this work helped clarify how mechanics contribute to cell behavior, showing that physical principles can be just as influential as biochemical signals.”
They then tested the model’s predictions by comparing them with experiments on mouse cells grown on materials with different stiffness.
The results hinge on integrin bond stability. On soft materials, bonds break quickly, leaving actin weakly anchored; it branches into a disorganized network that generates weak pushing forces and limits spreading. When bonds last longer—whether on stiff substrates or through experimental stabilization—actin filaments stay anchored, align into bundles, and generate stronger forces that drive membrane movement and cell spreading.
“The key result is that increasing integrin bond lifetime alone is enough to produce this reorganization,” says Sondaz. “You don’t need to change the stiffness of the environment if the bond stability is increased. You still see aligned actin and increased spreading.”
To test their model, the researchers compared its predictions with high-resolution microscopy images of real cells. Cells grown on soft materials showed branched, disorganized actin networks. In contrast, cells grown on stiff materials or soft materials with stabilized integrins formed highly aligned actin bundles. Measurements of actin alignment in these cells closely matched what the model predicted.
“We were able to show that this is a self-reinforcing process,” Bidone says. “Once adhesions are stable, they promote actin alignment and that alignment increases force and spreading, which further stabilizes the system.”
These findings have implications for a wide range of biological processes and diseases. Cell spreading and migration are central to wound healing, tissue development, fibrosis and cancer progression. In cancer, for example, integrins are often overexpressed, and tumors actively stiffen their surrounding tissue, creating feedback loops that promote invasive behavior.
“In diseases like cancer and fibrosis, cells respond to stiffness and then amplify it,” says Sondaz. “Understanding the mechanical rules that govern this response helps explain how those feedback loops form and persist.”
While the research is fundamental and not aimed at immediate clinical applications, it identifies integrin-matrix bond lifetime as a critical control point in cellular mechanosensing. Most existing therapeutic approaches target chemical signaling pathways. This work highlights the importance of physical interactions and mechanical regulation in shaping cell behavior.
“This study doesn’t replace the role of chemistry or signaling,” says Bidone. “What it shows is that mechanics alone can be sufficient to drive major structural changes in cells.”
By combining computational modeling with experimental validation, the research team provides a mechanistic framework for understanding how cells translate mechanical cues into organized force generation and shape change. The results offer a foundation for future research exploring how mechanical regulation contributes to health and disease across many biological systems.