Brown University Research Team Finds Keys To Liver Development

Understanding how to control both tissue growth and cell identity may lead to new disease-fighting methods that would rely on tissue regeneration and the ability to reprogram diseased cells into normal ones.

"This basic research won't translate into a cure tomorrow, but opens the way to think about new mechanisms of dealing with certain tissue degenerative diseases, particularly of the liver," said Ken Zaret, professor of molecular biology, cell biology and biochemistry in the Brown School of Medicine. "The liver is a critical organ and a target for viral hepatitis, alcoholism, metabolic diseases and cancer."

The experiments were conducted using undifferentiated cells, called endoderm cells, removed from the inner layer of mouse embryos. In the developing mouse, these endoderm cells have the potential to become a liver, pancreas, or other gut organs, based on the signals received.

In the June 18 issue of Science, Zaret and colleagues describe the signaling mechanisms that initiate these unspecialized embryonic cells to begin liver formation. The researchers developed the techniques to sift through tiny fragments of tissue to identify the relevant signaling factors. In doing so, they found that the fibroblast growth factors FGF1 and FGF2, and to some extent FGF8, begin the liver development process by differentiating the multi-potential endoderm cells into liver cells. FGF8 also helps prompt the cells to begin growing and forming liver tissue.

"Three signals are being conveyed to make sure that the liver appears at a specific time and place," Zaret said. "Thus there is a high degree of FGF signaling redundancy during liver specification."

Scientists have known that FGF signaling is important elsewhere in the body, where it prompts organ growth after initial specification by other growth factors. This study is the first to associate FGF signals with the initial specification of organs derived from gut endoderm such as the liver, pancreas, lung, stomach and thyroid. Zaret and colleagues hope to conduct further research to test whether these liver-formation signaling mechanisms influence the initial development of other cell types.

In the course of their work, the researchers isolated endoderm cells that are the explicit forerunners to the liver.

"We are working with the true embryological precursors to the liver, allowing us to study how cells go down that particular pathway," Zaret said. "With this lineage of definitive precursor cells, we have a chance of advancing the field of stem cell biology."

The study's lead author is graduate student Joonil Jung. The other authors are Zaret, former graduate student Minghua Zheng, and Mitchell Goldfarb, of the Mount Sinai School of Medicine. The work was funded by the National Institutes of Health.