Researchers outline how cells activate to cause fibrosis and organ scarring

New research led by Unity Health Toronto that examines how fibroblast cells in the body are activated to cause fibrosis and organ scarring has been published in Nature Reviews Molecular Cell Biology. Fibrosis and organ scarring are leading causes of death, with data suggesting they are responsible for up to 45% of deaths in the developed world.

Fibrosis is a process by which fibroblast cells in our body produce an excess amount of a protein mixture called extracellular matrix (ECM). ECM contains proteins including collagen, elastin and fibronectin and can be thought of as a sort of “glue” at the organism level that connects the different organs of our body while respecting their boundaries.

Typically, fibroblasts produce ECM to help support tissue structures and to help repair tissue that has been injured or wounded. For example, under normal circumstances, when you cut yourself, fibroblasts will travel to the site of the cut or wound, proliferate and produce ECM to help heal the cut. With fibrosis, however, fibroblasts receive certain signals which activate them to overproduce ECM.

This excess ECM, in particular the excess collagen, can result in the formation of scar tissue which can impair organ function. Fibrosis can occur in any tissue or organ in the body, including the lungs, liver, kidney and heart, and is associated with many common diseases—often as an end-stage condition.

The new research review summarizes some of the signals and molecular mechanisms that play a role in activating fibroblasts to produce excess ECM. The researchers also discuss the heterogeneous nature of fibroblasts, and how their vast heterogeneity can impact the healing process.

“This review tries to untangle some of our knowledge and understanding—or misunderstanding—of fibroblasts and fibroblast activation,” said Dr. Boris Hinz, corresponding author of the study and scientist at the Keenan Research Center for Biomedical Science at St. Michael’s Hospital.

“We generally talk about activation of fibroblasts from a dormant state in normal healing and fibrosis. But the cells activated to make new ECM were neither really dormant, nor are they all fibroblasts,” said Hinz. “We wanted to understand which cells in particular are activated. What types of activations take place—for example, “What are the key signals that activate these fibroblasts and how?'”

Fibroblasts remain ‘switched on’

Ph.D. student Fereshteh Sadat Younesi helped lead the review. Younesi is a member of Hinz’s lab and is a student at the Research Training Center at St. Michael’s Hospital.

“One key signal arises from the mechanical cues present in the stiffened environment of fibrotic regions. When tissues undergo fibrosis, they become way stiffer than normal because of these fibroblasts going into overproduction and rearranging the ECM,” Younesi said.

“Those fibroblasts can feel the stiffness around them, which keeps them switched on, even after the initial injury has healed. These mechanically induced fibroblasts exacerbate the fibrotic area with their persistent activity.”

Hinz said once researchers have a better understanding of the signals and mechanisms involved in fibroblast activation, they can develop therapies and interventions to interrupt the process and stop the overproduction of ECM, thus halting fibrosis.

“We need a cure for fibrosis. Scientists have known about fibrosis for roughly a century and there still is no cure,” Hinz said. “With only two currently approved drugs, we can only stop fibrosis in some organs—at best. An end goal would be to instruct the scar-making cells to remove excess ECM with pharmaceutical guidance. This is where the science is going and this is the ultimate dream.”