Texas A&M researchers discover protein to prevent DNA damage during liver regeneration
Researchers at the Texas A&M Health Science Center (TAMHSC) Institute of Biosciences and Technology (IBT) in Houston’s Texas Medical Center have uncovered a new mechanism for protecting the genetic integrity of actively dividing cells in the liver – a finding that could improve treatment and recovery in adult tissue or organs after injury. The study is available online and in the December edition of Hepatology, the official Journal of the American Association for the Study of Liver Diseases.
“Stem cells and cancer cells have the unique ability to maintain an extended reproductive lifespan compared to most other cells in the body,” explains Robert Tsai, M.D., Ph.D., associate professor in the Texas A&M IBT Center for Cancer and Stem Cell Biology and principal investigator of the study. “We applied this understanding to adult tissue regeneration to discover why this proliferating trait is not present in all tissue.”
The liver, one of the few human solid organs capable of natural regeneration, has a remarkable ability to recover lost tissue after injury or damage. During liver development and regeneration, hepatocytes, or liver cells, undergo rapid cell division, which increases the risk of damage to the genetic blueprint (or genome) and limits the reproductive lifespan of liver cells.
“Duplication of the genome during cell division is a critical period during a cell’s life cycle,” Tsai says. “An unrepaired part of the genome can cause catastrophic genetic error and disease.”
In an earlier study, the team found nucleostemin – a protein that regulates the reproductive potential of cells – plays an important role in preventing DNA damage during neural stem cell replication. Although the amount of nucleostemin is typically low in adult livers, Tsai notes, it increases considerably during liver damage caused by toxin or surgery, which prompted his latest work.
The team used an animal model to determine how the loss of nucleostemin would affect liver regeneration in response to injury. Their results show that removal of this protein significantly increased the amount of genetic mistakes in the newly regenerated adult liver cells, and that these mistakes eventually caused liver cell death, slowed down the regeneration process and impaired liver function. This discovery confirms the importance of nucleostemin and its role in preventing damage in the genetic blueprint of newly born liver cells.
“Our findings prove this mechanism is critical for the adult liver when undergoing the regeneration process,” Tsai says. “The adult liver is typically mitotically quiescent – or inactive – but under certain circumstances, such as toxin-induced injury or surgical removal of liver mass, the hepatocytes re-enter the cell cycle and become proliferative. Essentially, the mechanism we discovered plays a crucial role in allowing these cells to regenerate without incurring damage to their genome.”
In fact, if nucleostemin is not present when the liver faces injury, DNA damage will occur, resulting in increased mutations that prevent the regeneration process and may even cause disease, including cancer.
The protein reveals an important understanding in the process of tissue regeneration in adults, holding promise for the future of tissue recovery and treatment in patients with liver, brain and muscle damage.
Next, the team hopes to make a direct connection of this mechanism’s impact on cancer formation, identify all the players involved in this process and look for potential interventions that could be used for future therapeutic applications.
Contributors to the study include Tao Lin and Wessam Ibrahim, graduate students at TAMHSC Institute of Biosciences and Technology; Dr. Cheng-Yuan Peng, from the School of Medicine, China Medical University; and Dr. Milton J. Finegold, from Texas Children’s Hospital and Baylor College of Medicine. Research was supported by a National Institutes of Health pilot grant and a Texas A&M Cancer Research Council Incentive Award.