MEOX1 as an Important Regulator of Fibrosis, and Target for Therapy
Researchers here report on the identification of MEOX1 as an important regulator of fibrosis. Fibrosis is the inappropriate deposition of collagen in tissue to form scar-like structures that disrupt function, a malfunction of the normal processes of tissue maintenance. Fibrotic diseases often have an inflammatory component, and the presence of senescent cells and their harmful pro-inflammatory, pro-growth signaling has been implicated in the development and progression of fibrosis in aged tissues. Numerous aged organs are characterized by disruptive fibrosis, and this manifestation of aging presently lacks good treatment options. We can hope that senolytic therapies to selectively destroy senescent cells will do well in clinical trials for this sort of condition, but it is always possible that other approaches will be needed.
Fibroblasts are key to normal organ repair and integrity; they're the most abundant cell in connective tissue and congregate at sites of bodily damage or disease. In many cases, their presence is beneficial. They help launch immune responses, mediate inflammation, and rebuild tissue. But in chronic disease, activated fibroblasts can continuously create scar tissue, impeding normal organ function. Researchers knew that in mice with heart disease, blocking a class of proteins known as BET proteins slowed fibrosis and improved heart function, although it wasn't clear which cell type in the heart was being affected. They also knew that BET proteins are needed throughout the body for many important functions, including normal immunity.
Researchers studied mice who developed heart failure, and treated them daily with a BET inhibitor for 1 month. The researchers used single-cell RNA sequencing and single-cell epigenomics to compare heart cells from mice before, during, and after the treatment, and correlate those results with heart function. While the scientists didn't find significant changes to heart muscle cells, they observed that the treatment induced striking changes in cardiac fibroblasts, which represent more than half the cells in the human heart. In particular, the researchers discovered that the gene MEOX1 was highly active in the mice with heart failure and that its levels dramatically dropped when the mice were treated with the BET inhibitor.
The findings point to the precise part of the DNA, regulated by BET, that is responsible for MEOX1 to be turned on in disease states. Using CRISPR genome-editing technology, the scientists showed that deleting this small part of the DNA prevented MEOX1 from being activated, even under stress. The team went on to show that blocking MEOX1 from being switched on had the same effects as a BET inhibitor - it blocks the activation of fibroblasts. The researchers also studied other organs that commonly become fibrotic with disease, and found that cellular stress led to higher levels of MEOX1 in human lung, liver, and kidney fibroblasts. "We hope this discovery provides an avenue to slow down or stop fibrosis in many settings."
Link: https://gladstone.org/news/flipping-molecular-switch-heart-fibrosis