Scanning electron microscopy (SEM) image of human mammary epithelial MCF10A cells (orange) sensing a laser-ablated micro-defect on a collagen type I extracellular matrix surface through filopodial protrusions. Scale bar: 1µm.
Image Credit: Hannah Zmuda, Department of Biomedical Engineering, Washington University in St. Louis, with support from the Washington University Cellular Imaging Center (WUCCI)).
Scientific Frontline: Extended "At a Glance" Summary: Cellular Micro-Defect Sensing and Migration Stalling
The Core Concept: Cells use tiny protrusions called filopodia to detect micro-injuries in the extracellular matrix, prompting them to temporarily halt migration to initiate the healing process.
Key Distinction/Mechanism: While traveling collectively or individually, cellular filopodia sense minute defects (a few microns wide) in the basement membrane's collagen IV. This detection causes the cells to stall for up to eight hours, depositing new extracellular matrix to repair the wound before continuing their movement.
Major Frameworks/Components:
- Filopodia: Tiny "feet" on the leading edge of cells responsible for sensing surface defects.
- Extracellular Matrix (ECM): The structural support system for cells, consisting of the basement membrane and the interstitial matrix.
- Basement Membrane: A protective barrier made of collagen IV where the stalling behavior is triggered.
- Interstitial Matrix: The layer beneath the basement membrane composed of collagen I; when exposed (as in cancer), filopodia do not trigger stalling, altering cellular response.
- Environmental Factors: The degree of stalling is influenced by the surrounding material's stiffness and the fluid medium's osmolality (differences in salt, sugar, and water).
Branch of Science: Cell Biology, Biomechanics, Mechanobiology.
Future Application: The findings could inform new strategies for wound healing, tissue regeneration, and potentially disrupting tumor invasion in cancer by manipulating how cells perceive and respond to their microenvironment.
Why It Matters: Understanding the precise mechanical and biochemical cues that govern collective cell migration is crucial for advancing treatments for conditions dependent on cellular movement, from basic tissue repair to preventing cancer metastasis.
Cells travel through the body both individually and in collective groups during development, in wound healing, and in diseases such as cancer. New research from the McKelvey School of Engineering at Washington University in St. Louis shows that cells can sense even the smallest defects, or micro-injuries, in the surface over which they are traveling, stalling long enough to begin the healing process.
Amit Pathak, professor of mechanical engineering and materials science, and members of his lab—including Hannah Zmuda, who earned a doctorate in biomedical engineering from McKelvey Engineering in 2025—found that the tiny feet on the leading edge of a group of cells can sense a defect of only a few micrometers in a membrane below the surface of the extracellular matrix, which supports cell growth and provides structure when tissues regenerate.
Groups of cells travel along the extracellular matrix (ECM), which features a basement membrane—a protective layer made from collagen IV that acts as a tissue barrier for organs—and an interstitial matrix, which is made of collagen I and sits below the basement membrane. These cells move along the ECM using tiny feet called filopodia, which are so sensitive that they can detect the smallest of defects in the basement membrane and stop for up to eight hours—but only when collagen IV is present.
“The filopodia were something we specifically were not looking for, but they turned out to be the things that control this sensing of these tiny defects in extracellular surfaces,” Pathak said.
Interestingly, when the filopodia sense collagen I or stiffer ECMs, they keep moving over the defect, Pathak said, demonstrating that a difference in stiffness is critical.
“In cancer, the basement membrane gets degraded completely, so the cells have access to collagen type I, which is the more native tissue,” Pathak said. “In tumor invasion, you want them to notice the gap and stop, because stalling is good in cancer. If the cells don't notice small wounds and keep going, that means there was no healing done. If they stall and deposit new extracellular matrix, they heal the wound and then move on.”
Zmuda, who held a prestigious National Science Foundation Graduate Research Fellowship, and the team also found that the environment around the cells affects how strongly the stalling spreads. In addition to the type of collagen present, the stiffness of the surrounding material and the osmolarity of the fluid medium play significant roles.
“When we culture cells in the body, the fluid is not all the same,” Pathak said. “There are differences in salt, sugar, and water, which has a huge effect on osmolality. This changes cell migration and defect sensing. The membrane changes their feet, and the filopodia change.”
The team conducted their research using human mammary epithelial cells, Madin-Darby canine kidney cells, and primary zebrafish keratinocytes derived from fish scales. They created the defects in the hydrogels via laser ablation and then imaged the movement using atomic force microscopy.
Pathak said the findings show the importance of studying how multiple extracellular cues, including protein types, stiffness, and osmotic conditions, alter subcellular mechanics and multicellular collective migration. Better understanding these independent influences will increase knowledge of basic biological processes in wound healing, development, and tumor invasion, he said.
Funding: This research was supported by funding from the National Institutes of Health (R35GM156571) and the National Science Foundation Graduate Research Fellowship Program (DGE-2139839 and DGE-1745038).
Published in journal: Cell Reports
Title: Microscale matrix defects suppress tension-dependent protrusions and stall collective cell migration
Authors: Hannah Zmuda, Diego Barra Avila, Ping-Hsien Lee, and Christopher Walter, and Amit Pathak
Source/Credit: Washington University in St. Louis | Beth Miller
Edited by: Scientific Frontline
Reference Number: cbio081626_01