VGLL3 as an Important Regulator of Fibrosis
Fibrosis is a feature of the age-related decline of many organs and tissues, notably the heart, kidney, and liver, among others. It is a malfunction of normal tissue maintenance in which excessive extracellular matrix is created, leading to scar-like deposition that is disruptive to tissue structure and function. Chronic inflammation and the presence of senescent cells appear to be important in the development of fibrosis, but as yet the medical community lacks a proven approach to reversal of fibrosis. Much of the research continues to focus on finding regulatory genes that might be targeted in order to disrupt the formation of fibrotic structures, as in the example here, rather than looking at root causes.
When an injury is on your skin, it shows up as a visible scar, but what happens when vital organs like your heart or liver are damaged and hardens? If left unchecked, it can lead to loss of mechanics and dangerous consequences. These changes in tissues are attributed to the extracellular matrix. The extracellular matrix is a web of proteins found in every cell in the body, and acts both like wires on a circuit that allow cells to communicate with each other, and the beams in a building, giving the organs its structure. Too much extracellular matrix makes the cell, and by extension the organ, tough and inflexible, a condition known as fibrosis. In simple terms, fibrosis is a stiffening of cells and tissue. Its health implications are profound, as it can lead to poor pumping by the heart or cirrhosis in the liver.
"Myofibroblasts are a group of cells that produce collagen, a common extracellular matrix protein. In diseased organs they are seen overproducing collagen. Once myofibroblasts appear in diseased organs, fibrosis proceeds in a snowball fashion. At the same time, myofibroblasts are responsible for proper wound healing."
To understand how myofibroblasts turn pathological, researchers looked at how different physical stimuli changes the expression of genes in these cells. They found consistent changes in the expression of one gene: VGLL3. Their study showed that after a heart attack, myofibroblasts in both mouse and human hearts express more VGLL3 protein which led to the production of collagen. VGLL3 was also expressed more in fibrotic mouse liver, suggesting it contributes to fibrosis in multiple organs. Conversely, preventing VGLL3 activation in mice led to far less fibrosis in these organs. The study further showed that the relationship between matrix stiffness and VGLL3 activation becomes a pathological positive feedback loop, in that a stiffer matrix triggers more VGLL3 activation, which triggers the cell to produce more collagen.