Researchers Identify Key Pathway that Could be Targeted to Prevent Pathological Fibrosis

Researchers Identify Key Pathway that Could be Targeted to Prevent Pathological Fibrosis

Researchers at Temple University Lewis Katz School of Medicine (LKSOM) have characterized a new pathway involved in fibroblast activation and myofibroblast formation, which provides clues as to how pathological fibrosis could be prevented.

In response to injury to connective tissue, cells called fibroblasts are activated. These cells differentiate into cells called myofibroblasts, which form the extracellular matrix (ECM). Along with fibroblasts, these cells play an important role in injury response and help to repair connective tissue and close wounds. In some cases, however, fibroblast activation and myofibroblast activity gets out of hand and leads to pathological fibrosis – Thickening and scarring of connective tissue. Fibrosis is a feature of several chronic diseases – Interstitial lung diseases for example.

The researchers have described a signaling process which regulates myofibroblast differentiation and fibrosis by reducing calcium uptake in mitochondria. The cellular changes triggered by the reduction in calcium promote anabolic pathways and upregulate a metabolite called α-ketoglutarate, which alters gene expression for the conversion of fibroblasts into myofibroblasts.

While myofibroblasts are needed to close wounds, these cells may persist and give rise to pulmonary fibrosis, liver cirrhosis, and can lead to heart failure.

“Our experiments show that the accumulation of fibrotic cells results directly from mitochondrial calcium-dependent genomic reprogramming involving α-ketoglutarate, which changes the structure of chromatin, or DNA packaging — a phenomenon referred to as epigenetics and that is important in regulating gene expression,” explained John W. Elrod, PhD, Associate Professor in the Center for Translational Medicine at LKSOM, and senior author of the study. “This the first time that extracellular signals directly modifying mitochondrial function have been linked to alterations in the cell nucleus for the generation of myofibroblasts.”

Now that a pathway has been identified which plays a critical role in myofibroblast formation, drugs that alter calcium uptake in mitochondria could be developed and used to treat a range of fibrosis diseases. The researchers are now focusing on studies on chromatin changes that maintain myofibroblasts in diseased tissues.

The study is detailed in the paper – Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation – which was recently published in the journal Nature Communications. DOI: 0.1038/s41467-019-12103-x

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