Discovery of Cell-cycle Arrest at Wound Sites May Lead to New Treatment Options

Researchers from the University of Illinois at Chicago (UIC) have discovered that senescence, a state of reproductive dormancy, or cell-cycle arrest, occurs at wound sites, a process that, until now, was only known to occur in cells that suffer DNA damage. Principal investigator Lester Lau, professor of biochemistry and molecular biology at the UIC College of Medicine, and his research team also report that senescence at the site of a wound plays an important role in breaking down and preventing the formation of excess scar tissue.

Joon-Il Jun, a postdoctoral fellow in Lau's lab and lead author on the study in Nature Cell Biology, found that when fibroblasts were recruited to the site of a skin wound, they entered senescence, a state that the researchers discovered is turned on by the protein CCN1. These senescent fibroblasts were “making proteins that degraded the extracellular matrix and accelerated the breakdown of collagen,” and they had stopped making collagen.

"The accumulation of senescent cells in the wound has the biological effect of inhibiting the formation of excess scar tissue," Jun said.

In mice with a mutated, non-functional form of CCN1, the fibroblasts at the skin wound did not enter senescence, and excessive scar tissue formed. However, Jun found that when he applied CCN1 protein topically to the skin wound, fibroblast senescence was triggered and scar tissue formation was limited.

This series of discoveries — that senescence is a normal wound-healing response in the skin; that senescence in the wound serves an anti-fibrotic function; and that CCN1 is the critical protein that controls this process — may be critical in understanding a wide range of conditions that relate to tissue scarring, according to Lau.

"For example, chronic injury to the liver from a number of causes, including viral infections, alcoholism, diabetes and obesity, leads to fibrosis and may progress to cirrhosis," Lau said. "After a heart attack, accumulation of scar tissue in the heart impairs its ability to pump efficiently."

The researchers add that the ability to control the formation of scar tissue could have real implications for the future of treating wound-healing disorders, including organ damage where functional tissue is replaced with scar tissue.