Newly Identified Cellular Process Critical to Fibrosis in Chronic Liver Injury
In a multi-institutional collaboration led by David R. Brigstock, PhD
, principal investigator, Center for Clinical and Translational Research
, scientists have identified the role of a particular micro-RNA in regulating the production of scar tissue in livers with chronic injury. Understanding the mechanisms behind scar tissue production could eventually allow scientists to minimize scarring and protect healthy liver function in individuals suffering from chronic liver injury by up- or down-regulating the cellular signals at work.
The micro-RNA that they studied, miR-214, could potentially also be used as a clinical biomarker to indicate the extent of liver damage in individuals with such problems. The team’s research uncovered a paradigm for the control of signaling in fibrosis-producing cells and was featured on the cover of the journal Hepatology in March.
Chronic liver injury affects more than 5.5 million children and adults with a wide range of health problems, including liver failure, hepatitis, autoimmune conditions, metabolic disorders and genetic diseases. Together with hepatic cancer, these liver diseases collectively constitute one of the 10 leading causes of death in the United States. Scarring, or fibrosis, is a common and debilitating problem that interferes with proper functioning of the liver, hinders effective treatment and increases the need for liver transplantation. Treatment or prevention of the scarring process could save thousands of lives.
“In healthy livers, we found that miR-214 was expressed in high amounts, but in damaged livers miR-214 levels were very low,” says Dr. Brigstock, principal investigator in the Center for Clinical and Translational Research and senior author on the paper. “When the liver functions normally, the high levels of miR-214 are responsible for suppressing the production of a fibrosis-promoting molecule called connective tissue growth factor. However, in settings of chronic liver injury, the reduced expression of miR-214 favors unrelenting production of connective tissue growth factor, which then drives a sustained and detrimental fibrotic reaction.”
The research team also found that miR-214 was released from cells in nano-sized vesicles called exosomes, which then delivered the miR-214 to neighboring cells to regulate scarring pathways. Assessing the levels of miR-214 and other molecules in exosomes from blood or urine holds immense promise for identifying biomarkers that could help investigators assess the extent of liver scarring and response to treatment, Dr. Brigstock says.
“Our immediate goals are to understand how miR-214 is switched off during liver disease and to establish the value of miR-214 and other exosomal micro-RNAs as fibrosis biomarkers,” says Dr. Brigstock, who also is a professor of surgery at The Ohio State University College of Medicine. “The identification of miR-214 as a suppressor of fibrosis suggests that it may have potential utility as a therapeutic agent in chronic liver disease, as well as in fibrosis in other vital organ systems such as the heart, lungs and kidney.”
“Perhaps even more important is our finding that fibrosis is regulated by exosomes,” Dr. Brigstock explains. “Understanding the molecular payload in exosomes could herald a new era in diagnosing and treating patients with life-threatening liver disease.”
Chen L, Charrier A, Zhou Y, Chen R, Yu B, Agarwal K, Tsukamoto H, Lee LJ, Paulaitis ME, Brigstock DR. Epigenetic regulation of connective tissue growth factor by MicroRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology. 2014 Mar, 59(3):1118-29. Epub 2014 Jan 27.