Tissue Regeneration Promoted through Gene Suppression

    Having a greater understanding of how certain tissues regenerate after injury would be extraordinarily useful in treating various diseases. Many animals have the capacity to regenerate entire appendages, such as tails in lizards and arms in starfish, yet mammals have all but lost the capacity to regenerate body parts extensively.

    Now, scientists at the Children’s Medical Center Research Institute (CRI) at the University of Texas Southwestern Medical Center report that inactivating an individual protein-coding gene promotes liver tissue regeneration in mammals.

    “This research gives us ideas about new ways to treat liver damage or chronic liver disease,” explained senior study author Hao Zhu, M.D., assistant professor at CRI.

    In mammals, the liver stands alone among solid organs in its robust regenerative capability. A healthy liver can regenerate up to 70% of its tissue after injury. However, when the liver has repeatedly been damaged—by chemicals or chronic disease—it loses its ability to regenerate. Following repeated injuries, cirrhosis, or scar tissue, forms, significantly increasing the risk of cancer.

    The National Cancer Institute (NCI) reports that liver cancer deaths increased at the highest rate of all common cancers from 2003 to 2012. In addition to cirrhosis, risk factors for liver cancer include infections caused by the hepatitis C virus (HCV), liver damage from alcohol or other toxins, chronic liver disease, and certain rare genetic disorders.

    Dr. Zhu’s team, which studies both cancer and tissue regeneration, began their investigation by studying mice that lacked Arid1a, the mouse version of a gene associated with some human cancers.

    The findings from this study were published recently in Cell Stem Cells in an article entitled “Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration.”

    “In humans, the gene ARID1A is mutated in several cancers, including liver cancer, pancreatic cancer, breast cancer, endometrial cancer, lung cancer, the list goes on,” Dr. Zhu noted. “It is not mutated in every type of cancer, but in a significant number. Those mutations are found in 10–20% of all cancers, and the mutations render the gene inactive.”

    On the basis of this scenario, the researchers postulated that mice devoid of Arid1a would develop liver damage and, eventually, liver cancer. They were astonished when the opposite proved to be the case—no liver damage occurred. In fact, livers of the mice regenerated faster and appeared to function better.

    “The livers were resistant to tissue damage and healed better, which are two good things—like playing offense and defense at the same time,” Dr. Zhu remarked. “These results opened up a whole new avenue of investigation for us, and through that investigation, we found a new function for this gene.”

    The researchers reported that mice lacking Arid1a appeared healthier, which was confirmed by improved liver function analysis. When Dr. Zhu and his team deleted the gene in mice with various liver injuries, they found that the livers replaced tissue mass quicker and showed reduced fibrosis in response to chemical injury. Moreover, additional tissues, such as wounded skin, healed faster in the Arid1a-deficient mice.

    Unfortunately, no drugs are currently available to mimic a lack of the Arid1a protein, although the researchers are working with other institutions to search actively for one.

    “We want to identify small molecules that mimic the effect of these genetic findings. The ideal drug would be one that helps the liver heal while inhibiting the development of cancer. That would be the perfect drug for my patients,” remarked Dr. Zhu.

    The CRI team believes that the loss of the Arid1a gene and the protein it expresses may accelerate regeneration by reorganizing how genes are packaged in the genome so that the cells can more easily switch back and forth toward a more regenerative state, sort of like a toggle switch.

    “Somehow, loss of this gene seems to make it easier for the cell to go back and forth,” Dr. Zhu stated. “This study opens up new areas to investigate how to rejuvenate tissues without necessarily increasing cancer risk, although many more tests will have to be done to determine how the risk of all types of liver cancers are altered.”