In a new study from Washington University, scientists are describing how the processes of wound healing and scarring are initiated. The unprecedented research could have major implications for treating conditions such as cancer metastasis and fibrosis.
While previous studies have documented how cells mobilize to heal wounds and how scars form, the specific mechanisms underlying this activity have remained a mystery to scientists.
For the current investigation, the research team was led by Delaram Shakiba, a postdoctoral fellow from the NSF Science and Technology Center for Engineering Mechanobiology (CEMB) at the McKelvey School of Engineering.
“Clinical efforts to prevent the progression of fibro contractile diseases, such as scarring and fibrosis, have been largely unsuccessful, in part because the mechanisms that cells use to interact with the protein fibers around them are unclear,” said Shakiba.
“We found that fibroblasts use completely different mechanisms in the early – and I think the most treatable – stages of these interactions, and that their responses to drugs can therefore be the opposite of what they would be in the later stages.”
Fibroblasts are common cells in connective tissue that interact with the extracellular matrix, which provides structural support as well as chemical cues to cells. The team found that these interactions are facilitated by a recursive process that takes place between the cells and their environment. The fibroblasts also use internal structures to communicate that were previously unknown, according to the study.
“Researchers in the field of mechanobiology thought that cells pulled in collagen from the extracellular matrix by reaching out with long protrusions, grabbing it and pulling it back,” said study co-senior author Guy Genin.
“We discovered that this wasn’t the case. A cell has to push its way out through collagen first, then instead of grabbing on, it essentially shoots tiny hairs, or filopodia, out of the sides of its arms, pulls in collagen that way, then retracts.”
Now that this process is understood, the shape that a cell takes during wound healing can be controlled, explained Genin.
“With our colleagues at CEMB at the University of Pennsylvania, we were able to validate some mathematical models to go through the engineering process, and we now have the basic rules that cells follow,” said Genin. “We can now begin to design specific stimuli to direct a cell to behave in a certain way in building a tissue-engineered structure.”
The researchers discovered that the cell shape can be regulated in two ways: by controlling the boundaries around the cell and by inhibiting or upregulating particular proteins involved in the remodeling of the collagen.
Fibroblasts pull the edges of a wound together, causing it to contract or close up. Next, collagen remodels the extracellular matrix to fully close the wound.
“There’s a balance between tension and compression inside a cell that is newly exposed to fibrous proteins,” said Genin. “There is tension in actin cables, and by playing with that balance, we can make these protrusions grow extremely long. We can stop the remodeling from occurring or we can increase it.”
The investigation was conducted using a 3D-mapping technique to examine collagen formation and a computational model to calculate the stress fields created by the protrusions from the cells.
The analysis showed that as the cells accumulated collagen, these fibers aligned under tension and formed collagen tracts that enabled the cells to interact mechanically.
“New methods of microscopy, tissue engineering and biomechanical modeling greatly enhance our understanding of the mechanisms by which cells modify and repair the tissues they populate,” said study co-senior author Professor Elliot Elson.
“Fibrous cellular structures generate and guide forces that compress and reorient their extracellular fibrous environment. This raises new questions about the molecular mechanisms of these functions and how cells regulate the forces they exert and how they govern the extent of matrix deformation.”
“Wound healing is a great example of how these processes are important in a physiologic way,” said Genin. “We’ll be able to come up with insight in how to train cells not to excessively compact the collagen around them.”
The study is published in the ACS Nano.