Highlights • Arid1a loss results in improved regeneration after diverse liver injuries • Arid1a overexpression impairs liver proliferation and regeneration • Arid1a loss also improves tissue repair after ear hole punch • Arid1a loss remodels chromatin, altering transcriptional access by C/EBPα and E2F4
The liver is unique among human solid organs in its robust regenerative capability. This research gives us ideas about new ways to treat liver damage or chronic liver disease,” said Dr. Hao Zhu, an Assistant Professor at CRI. Tails in lizards and arms in starfish show an astounding ability to regrow, but mammals have partially lost the capacity to extensively regenerate body parts, Dr. Zhu said. The liver is unique among human solid organs in its robust regenerative capability. A healthy liver can regenerate up to 70% of its tissue after injury, he explained.
However, when the liver has been repeatedly damaged – by chemical toxins or chronic disease – it loses its ability to regenerate. Following repeated injuries, cirrhosis or scar tissue forms, greatly increasing the risk of cancer, said Dr. Zhu, who also treats liver cancer patients at Parkland Memorial Hospital. The Zhu laboratory studies both regeneration, when cells proliferate to repair an organ, and cancer, when cells proliferate out of control.
The National Cancer Institute (NCI) reports that liver cancer deaths increased at the highest rate of all common cancers from 2003-2012. 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 studied a mouse that lacked Arid1a, the mouse version of a gene associated with some human cancers. “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 said. “It is not mutated in every type of cancer, but in a significant number. Those mutations are found in 10 to 20% of all cancers, and the mutations render the gene inactive.”
No liver damage occurred in these mice. In fact, livers of the mice regenerated faster and appeared to function better, he added. “The livers were resistant to tissue damage and healed better, which are two good things – like playing offense and defense at the same time,” he said. When researchers 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. Also, other tissues such as wounded skin healed faster in Arid1a-deficient mice.
“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,” said Dr. Zhu, a CPRIT Scholar in Cancer Research. Loss of the 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. http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/march/zhu-liver-regeneration.html
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