Solving the Two-Thousand-Year-Old Mystery of Liver Regeneration
Scientists have known since ancient times, as notable in Greek mythology, that liver tissue has a remarkable ability to regenerate, but embryologist Kim Tremblay, veterinary and animal sciences, says, “We still don’t know how it does that, it’s still a mystery even after two thousand years.”
She now has a five-year, $1.4 million grant from the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases to investigate how the organ can replace itself in an amazingly short time. “Unlike any of our other organs, if you cut out two-thirds of your liver, it will grow back in seven days,” she says. “What’s amazing about that time is that in many organisms that have a liver, it can grow back in seven days.”
The liver filters impurities, toxins, alcohol and drugs, for example, from the bloodstream, which kills many cells, so in a sense it’s not surprising that the organ can quickly respond to injury by making new ones, Tremblay says. “There is a reservoir of cells that replace the dead ones. The liver has a huge number of regenerative or homeostatic cues that trigger this, but we have not yet established which cells are responsible for this.”
As a developmental biologist, Tremblay will focus on how hepatic cell types emerge during embryonic development. Using this strategy, she hopes to address long-standing disagreement in the field regarding the cells that are involved in regeneration. “Some scientists think it’s one type, others insist it is another,” she says, “but the problem is that they are often using different regeneration models. What if adult cells are able to respond to distinct regenerative cues in unique ways because of where or how they arose in the embryo?”
In the embryonic liver bud, she explains, embryonic precursor cells called hepatoblasts differentiate into two distinct adult cell types – hepatocytes and cholangiocytes. Researchers have “varying views” about which of these might hold the regeneration key. “We do know they arise in different developmental pathways in the embryo and they look different in an adult,” Tremblay adds.
“Unlike any of our other organs, if you cut out two-thirds of your liver, it will grow back in seven days. What’s amazing about that time is that in many organisms that have a liver, it can grow back in seven days,” says Tremblay.
Her previous experiments in a culture system she developed show that hepatoblasts, the hepatic precursor cells, respond differently to cues – growth factors and other signals – in the embryo. Tremblay believes that a new series of investigations in a mouse liver model using targeted genetic techniques will show that both cell types harbor more than one as-yet-undiscovered variant.
“I think we haven’t yet discovered the differences within those groups,” the embryologist says. “The grant is designed to explore this heterogeneity in development. We’ll use RNA transcript analysis from knock-out mice to identify the roles of particular genes, and we’ll also explore ATAC-Seq.” ATAC-Seq is a sensitive technique used to look for epigenetic memory, which is where Tremblay hypothesizes that her lab will find the key to how the different cells arise.
“So far, the work in our lab has focused on the liver bud around 9.5 days of development,” Tremblay says. In the future, “we want to study the process later in development but still in the embryo.”
“By 10.5 days the liver is composed of hepatoblasts in lobes, and a slightly later cells start going down the path toward becoming hepatocytes or cholangiocytes. That’s when we’ll look at the different RNA transcripts, but I think we’re going to find that the answer has to do more with epigenetics and the different environmental signals the precursors are exposed to. Because developmentally acquired epigenetic traits can be maintained through adulthood, it could provide a mechanism that would explain why some adult liver respond to certain injuries better than others.”