Researchers identify genetic mutations that can promote regeneration after liver damage

Researchers at the Research Institute of UT Southwestern Children's Medical Center (CRI) have identified genetic mutations that accumulate in the adult liver and may promote regeneration in the context of chronic liver injury.

Watch the video: Researchers demonstrate that mutations in the human liver can promote tissue regeneration

The widespread use of genome sequencing has made it possible to realize that normal tissues in healthy people accumulate spontaneous changes in DNA, called somatic mutations, over time. This process has been well characterized in the blood-forming system, but it is not known to what extent somatic mutations accumulate with age in most solid organs, nor what effect this accumulation might have on the regeneration of organs.

"The mutations that occur in normal cells are most often seen through the lens of cancer.While some mutations may represent a stage in the development of cancer, others may actually promote healing of tissues without causing cancer, "said Dr. Hao Zhu, Associate Professor. CRI and Internal Medicine and Pediatrics at UT Southwestern. Dr. Zhu, corresponding author of the study published today in Cell, is also a treating physician at the Parkland Hospital Multidisciplinary Liver Cancer Clinic.

Researchers used various genetic techniques to identify mutated genes in patients with chronic liver disease and to badess whether mutations affected liver cell function. The study of somatic mutations in normal tissues being still a relatively new field, Dr. Zhu and his collaborators first had to develop some of the genetic techniques used to make these discoveries.

"Cancer sequencing has been done for a long time, but normal tissue sequencing is still new for many researchers, and in the absence of a predefined method for identifying mutations in normal tissue, we have had to develop ours." , said the corresponding co-author, Dr. Tao Wang, an badistant professor of population and data sciences and the Center for Defense Genetics host at UT Southwestern. Dr. Wang, a member of the University's Center for Quantitative Biomedical Research, and graduate student Tianshi Lu, have developed computational methods to badyze the sequencing data generated in this study.

These approaches allowed researchers to find hundreds of mutations in liver samples obtained from Parkland Hospital patients by co-authors Drs. Adam Yopp, Associate Professor of Surgery at UTSW, and Amit Singal, Associate Professor of Internal Medicine and Population and Data Sciences at UTSW. The researchers then used a new CRISPR genetic screening method on mouse liver to test the functional consequences of mutations on liver regeneration. This research has identified a handful of mutations that have had pronounced effects on liver regeneration.

"The CRISPR screening method developed by Joyce Jia, a graduate student in my lab, was an essential part of the study that allowed us to identify important genes among a large number of candidates. not only allowed to examine the impact of We hope to use it to find new drugs that would increase the regeneration of organs in humans, "said Dr. Zhu.

Then Dr. Min Zhu, one of the co-first authors of the study, suppressed the highest ranked genes in the liver of mice to mimic the effects of the mutations seen in human liver samples. The researchers found that these genetically modified livers were more regenerating after liver damage.

"We found that many mutations provide liver cells with benefits to their shape, giving them an advantage over unmutated cells in terms of growth and survival after environmental stress," said Dr. Hao. Zhu. "However, the most remarkable conclusion of our study is that some mutated genes that have a strong influence on regeneration are unlikely to favor cancer because they are rarely mutated in liver cancer samples." This finding suggests that some mutations are selected from regenerating tissues for chronic lesions that promote regeneration or tissue development without promoting cancer development. "

This result is surprising, since chronic tissue damage promotes the development of cancer, especially the liver, he added.

These results have implications for patients with chronic liver disease. Currently, these patients have few therapeutic options and are at risk of developing liver cancer, one of the fastest growing causes of cancer death in the United States. Understanding whether the frequency and type of mutations can predict cancer risk may one day allow physicians to identify patients at higher risk of liver cancer and increase their incentive to detect or prevent cancer. . In addition, a better understanding of how mutated genes promote tissue growth and regeneration, without promoting cancer, could enable scientists to develop therapies to safely prevent the progression of liver disease.