Science magazine has put the report on its fast track for publication and will release it Thursday, Sept. 27 on its web site www.sciencemag.org/.
Zaret heads Fox Chase's basic science program in cell and developmental biology. The goal of his research focuses on understanding how genes are activated and how early embryonic cells become specific tissue types during the development of mammals. One of his laboratory models uses mouse embryonic cells known as endoderm cells, which have the potential to become a liver or pancreas. Zaret has identified molecular signals that tell these cells where and when a liver should appear. Recently, he has learned to use those signals to direct immature cells in culture to begin liver formation.
His newest study explores the early developmental role of endothelial cells, which normally make up blood vessels. Previously these cells were believed to promote tissue growth by providing oxygen, nutrients and blood cells to tissue sites. Instead, Zaret’s group has shown that endothelial cells promote tissue growth and development even before functioning blood vessels arise. Before they begin to ferry blood to organs, early blood vessel cells emit signals that encourage the growth of the newly emerging liver and possibly other organs, such as the lung and pancreas. "We now show there is an intrinsic function of the endothelial cells prior to the functioning of vessels," Zaret said. "The development of internal organs requires the careful orchestration of signals between endothelial cells and the cells intrinsic to each tissue." The experiments used embryonic mouse cells with mutations in a gene responsible for these signals. The developing embryos not only lacked endothelial cells but also failed to develop a liver. Additional studies show that this essential role of endothelial cells appears to extend to lung and pancreas organogenesis. According to the Science report, "the early stages of visceral organ development serve as a model for changes in cells and tissues that occur in various biological contexts…organogenesis, tissue regeneration and tumor growth." "Understanding how endothelial cells promote early organ development may enhance our understanding of these other processes," Zaret noted.
"The new embryonic cell culture techniques we describe may further future efforts to reconstitute organ systems in vitro, for basic research and drug studies, and within living beings for therapeutic purposes or for artificial organs," he added.
Since the liver is a target for chronic diseases such as hepatitis and for the spread of many cancers, this ongoing research has the potential for a significant impact on combating disease. For example, more than 18,300 people in this country are awaiting a liver transplant, including many who have been on the waiting list for more than two years, according to the United Network for Organ Sharing.
Zaret holds the William Wikoff Smith Chair in Cancer Research at Fox Chase. A grant from the National Institute of General Medical Sciences at the National Institutes of Health supports his research.
Judith H. Greenberg, Ph.D., director of the NIGMS division of genetics and developmental biology, said of the new study: "As was the case with Dr. Zaret’s recent results on factors that regulate the development of the embryonic pancreas and liver, his new work demonstrates beautifully how basic research findings can guide the development of novel approaches to treat diseases." Co-authors for this study are Kunio Matsumoto, Ph.D., of Osaka University Graduate School of Medicine’s division of molecular regenerative medicine in Japan; Hideyuki Yoshitomi, M.D., Ph.D., a postdoctoral fellow at Fox Chase; and Janet Rossant, Ph.D., of the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto.
Fox Chase Cancer Center, one of the nation’s first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center’s web site at www.fccc.edu or call 1-888-FOX CHASE.
Journal
Science