AMHERST, Mass. – At present, medical researchers lack experimental models and urgently need new ways to study liver function and mechanisms, especially because liver disease is on the rise due to the obesity crisis, and late-stage disease often requires an organ transplant. Now researcher Kim Tremblay at the University of Massachusetts Amherst has received a grant to develop a promising new model liver system.
A developmental biologist, Tremblay recently received a two-year, $426,000 grant from NIH’s National Institute of Diabetes and Digestive and Kidney Diseases to use extra-embryonic tissue, that is, the membranes and tissues that protect and nourish embryos until birth, to develop a new model liver system.
She says, “I studied extra-embryonic tissue as a graduate student, a postdoctoral researcher and now in my own lab, so over time I’ve became an expert in the yolk sac and other extra-embryonic tissues. At some point I began to think critically about their similarity to the early liver. I’ve come to realize that these under-appreciated tissues offer a much more readily available, simpler model for liver development research.”
During the earliest stages of embryo development, she explains, the embryo’s protective yolk sac acts just like an early gut, carrying out the same blood-purifying tasks as the liver does at later developmental stages. Unlike developing liver tissue, however, the yolk sac is on the outside, thus more accessible as it surrounds the embryo. Compared to the early liver, the yolk sac is “huge,” she adds, offering many more cells that are more easily freed from the surrounding blood vessels.
The yolk sac “intimately interacts with the vasculature,” Tremblay says, “but there is a really easy way to separate them at this stage, to isolate the yolk sac and pull the tissue layers apart with a simple enzyme process. It requires no special manipulations, and the result is two pure tissue types available for transcriptional profiling and similar studies,” she adds.
“I hope to demonstrate that the yolk sac is far more valuable than many researchers had previously thought, and that it can act as a very useful proxy for studying the early liver. It’s interesting that discussion of the yolk sac peppers the literature, but the yolk sac has been of no interest to most researchers, they just toss it. But in fact, almost every gene that is essential to early liver development is first essential in the yolk sac. I believe we need to be taking a closer look at how it can help us.”
One question researchers would like to answer is how hepatoblasts, embryonic cells that will become the liver, communicate so effectively with surrounding cells that form the vascular blood vessel network. Hepatoblasts and vascular tissues, as well as the yolk sac and its vascular network, essentially develop together, in very close coordination.
Specifically, Tremblay will study a particular gene known as Yin Yang 1 (YY1), which has a dual nature, stimulating and inhibiting certain growth processes. She and colleagues have shown that when YY1 is knocked out in yolk sac cells, they lose their identity and cannot communicate with surrounding blood vessels, so these don’t form properly.
“We see exactly the same thing in liver cells” she says, “Which supports the view that in each case, tissues are unable to communicate with the vasculature in the same way as when YY1 is present.” Tremblay hopes that future advances in using extra-embryonic tissue may lead to growing liver tissue in glass dishes, making it easier for researchers to study function in a simple system that is much better suited to analytics such as transcriptome and proteome analysis.