September 18, 1998

Investigator probes secrets of liver’s regenerative powers

Investigator probes secrets of liver's regenerative powers

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A three-year grant from the NIH is helping Dr. William Russell investigate liver development. (Photo by Donna Jones Bailey)

Dr. William E. Russell, associate professor of Pediatrics and Cell Biology, has been awarded a three-year grant from the National Institutes of Health to investigate liver development, including the organ's unique ability to regenerate itself.

"Unlike all other internal organs in mammals, the liver has a remarkable capacity to regenerate itself," Russell said. "After a lobe of the liver has been surgically removed or is injured by drugs, chemicals or viruses, the various cells that make up the liver proliferate rapidly to replace the lost tissue. Remarkably, this compensatory hyperplasia terminates precisely after restoring the liver to exactly its original size."

The ultimate goal of Russell's research is to determine how the EGF receptor family is involved in the regeneration process after liver tissue has been damaged. To accomplish this, he will study how the EGF receptor signaling system develops during gestation, as well as how it operates in the adult liver.

"Due to its widespread roles in metabolism and detoxification of the body, proper functioning of the liver is essential to health and survival," Russell said. "Studies of how growth factor signaling systems evolve in the developing liver may aid in the generation of mature hepacytes and other liver cells from undifferentiated precursor cells, perhaps making possible the production of artificial livers for temporary life support."

According to Russell, understanding how the liver is able to regenerate could serve as a model for investigating other processes, such as wound healing and cancer formation.

Although no single agent has been shown to trigger this regeneration, cellular proliferation involved in the process is believed to require a family of growth factors that includes epidermal growth factor (EGF), along with activators of the EGF receptor, such as transforming growth factor alpha (TGFa).

Not only do the levels of TGFa and other related mitogens rise in the liver immediately after injury, but liver cells also contain the highest density of EGF receptors of any cells in the body. This suggests that activation of the EGF receptors may be important in regeneration, Russell said.

Further evidence implicating the receptor in liver regeneration is that the first cells to begin cell division after partial hepatectomy are hepatocytes adjacent to the portal vein, where there is a high concentration of EGF receptors.

Until recently, researchers believed that EGF acts upon target cells solely via the EGF receptor. The current consensus, however, is that EGF signaling involves complex interactions among EGF receptors and other receptors, a process known as heterodimerization. This process is thought to be necessary for the optimal relaying of the growth-stimulatory signal carried by TGFa and related growth factors.

Previous studies have shown that ErB2, the receptor Russell's lab plans to focus on, is the preferred heterodimerization partner of all the members of the EGF-related receptors.

"We hypothesize that ErB2 is a development switch for EGF receptor signaling as the organism matures," Russell said.

Present during embryonic development, ErB2 is no longer expressed in adult animal models, an absence Russell said accounts for the non-responsiveness of the 'dormant' adult liver cells with respect to cell division.

The majority of previous studies of ErB2 were conducted in vitro. Russell's approach will be to use two unique strains of test mice, one of which lacks EGF receptor and another which lacks ErB2 receptor. Normally, these mice die early in development due to malfunctions of other organs. To circumvent this problem, chimeric mice are being engineered in collaboration with Dr. David Threadgill, assistant professor of Cell Biology.

The organs, including the livers, of these genetically engineered mice will contain a mixed population of normal and EGF- or ErB2-receptor-deficient cells. The presence of some normal cells possessing the critical receptors will prevent mice from dying prematurely. This will enable the development of liver cells lacking EGF or ErB2 receptor to be compared to that of normal cells.

Russell will also examine the pattern of ErB2 expression in normal mice, particularly the timing of its disappearance from adult mice and subsequent anticipated reappearance following liver damage. In addition, Russell will perform experiments on cultured cells in order to further assess whether the maturation of liver cells coincides with ErB2 expression.