Extracellular Matrix Not Seen as Direct Cause of Cell Aging in IPF

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by Forest Ray PhD |

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Alterations in the extracellular matrix — the network of molecules that surrounds and supports cells — and cell aging, a process of called senescence, both contribute to tissue scarring in idiopathic pulmonary fibrosis (IPF), according to a recent study.

Yet, matrix changes do not lead to senescence, implying that these processes act independently of each other to promote scarring or fibrosis.

The study, “Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM,” was published in the journal Cells.

Changes to the extracellular matrix, as well as cellular senescence — which prevents cells from multiplying — contribute to the lung fibrosis that characterizes IPF.

While senescence is known to play a role to IPF progression, whether changes to the extracellular matrix can cause cells to become senescent, thereby creating a positive feedback loop driving fibrosis, remains unclear.

Two cell types relevant to IPF — alveolar epithelial cells and fibroblasts — show signs of senescence over the course of the illness. Fibroblasts also have a key role in maintaining the matrix and remodeling it as needed.

Researchers with the University of Groningen in the Netherlands and their colleagues set out to determine whether the extracellular matrix of fibrotic tissues could trigger senescence in lung fibroblasts. To do so, they compared what happens to these cells when grown in conditions that favor fibrosis or favor senescence.

They used lung fibroblasts taken from either IPF patients or individuals who did not the disease (control group); all while undergoing either a lung transplant or surgery to remove a tumor. The research team then grew these cells in the presence of an extracellular matrix derived from IPF patients and from controls. Each type of matrix was also pre-treated with or without specific factors to provoke fibrosis or senescence.

Neither the control-derived matrix nor that from IPF patients caused fibroblasts to become senescent.

“This is the first study to show that ECM [extracellular matrix], by itself, does not induce senescence in fibroblasts,” the researchers wrote.

When fibroblasts were grown in an extracellular matrix that had been treated to mimic active fibrosis, they produced several pro-inflammatory proteins involved in early wound repair, indicating that cells had been engaged in a wound healing response. These cells also started producing higher amounts of the fibrosis-associated proteins transforming growth factor beta 1 and connective tissue growth factor.

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They did not, however, produce more cross-linking enzymes, in contrast to at least one previous study. These enzymes help to bind matrix components together, which contributes to fibrosis by making the extracellular matrix too thick and stiff to allow healthy cell growth and movement.

Investigators suggested that increased cross-linking could be a later feature of IPF, which takes years to develop. Other known IPF contributors, such as reactive oxygen species (ROS; also known as free radicals), might be needed to create an environment that favors senescence.

Overall, this study demonstrated that the extracellular matrix alone does not induce cellular senescence, although it can trigger pro-inflammatory and pro-fibrotic protein activity.

“These data suggest that, to induce a strong response to their environment, not only is composition important in IPF but a secondary stimulant that induces DNA damage such as ROS, or pathological [disease-associated] stiffness might be required to create a positive feedback look that perpetuates fibrosis in IPF,” the researchers concluded.

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