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July 17, 2003 - Scientists Report Key Discovery in Organ Development

For Immediate Release: Thursday, July 17, 2003
Contact: Bob Kuska, (301) 594-7560

Within weeks of fertilization, one of the great mysteries of life occurs: The heart, lungs, kidneys, and other organs begin to appear in the fetus. Many start out as a tube-shaped sheet of cells, which then bud and branch anew hundreds to millions of times before reaching their final three-dimensional shape. Although scientists have identified many proteins that are present as organs develop, they know little about how these molecules interact to catalyze the process, information that is vital in learning one day to efficiently engineer replacement organs.

A team of NIDCR scientists recently made a critical discovery that helps to explain in part how the process works. Reporting in the June 19, 2003 issue of Nature, the scientists found that cells in certain areas of the bud secrete the protein fibronectin, which helps to create a deep indentation, or cleft, in the bud. These clefts serve to subdivide the single bud into several smaller buds, freeing them to branch in different directions and form increasingly more intricate, preprogrammed three dimensional patterns.

Intriguingly, the scientists found they could double the rate of branching when they added fibronectin to organ cultures depleted of the protein. This finding suggests a specific biological mechanism that bioengineers can exploit in future studies to spur the natural growth of many developing organs.

Kenneth Yamada, M.D., Ph.D., senior author on the paper, noted that their discovery occurred first in animal studies of the developing submandibular salivary gland, located on the underside of the jaw. Yamada said his group extended their work to the developing lung and kidney, where they found the protein also was essential for clefting. “This is one more example of the value of studying the craniofacial region,” said Yamada. “Oral tissues are relatively easy to access, and so many of the biological principles that we discover there are applicable in other parts of the body.”

According to Yamada, the Nature paper grew out of preliminary work in which the group identified several genes that were expressed at higher levels in the developing cleft, an indication that their protein products might be important in forming the cleft.

Among the names on the list was fibronectin, a single gene that encodes a variety of adhesive structural proteins generally involved in holding cells in position and guiding their migrations. “We’ve studied fibronectin in the past,” said Yamada, who, in fact, published a number of important early papers on the gene and its proteins. “So, we just jumped on it.”

First, the group compared expression levels of the fibronectin gene in the cleft with those elsewhere in the bud. This confirmed their previous finding, reporting that fibronectin was expressed 16-fold higher in the cleft. They also discovered thereafter that, in the area immediately adjacent to where the fibronectin protein localized, cell to cell adhesion was decreased, which one might expect if a cleft was forming.

“At this point, we hypothesized that, after the transient, local expression of the protein, cells in the general area stop adhering to each other and begin attaching to a fibronectin matrix, which serves as the structural framework of the developing cleft,” said Takayoshi Sakai, D.D.S., lead author on the study.

Putting their hypothesis to the test, Sakai et al. successfully demonstrated in follow-up organ culture studies that the development of the submandibular salivary gland is severely inhibited when fibronectin is not present. They also showed that, without fibronectin, the budding and branching process is either nonexistent or substantially decreased.

“In other organs, especially the kidney, it’s been shown previously that the budding and branching seems to differ in the relative contribution of bud outgrowth compared with cleft formation,” said Melinda Larsen, Ph.D., an author on the study. “Nevertheless, in our studies with lung and kidney, we also found a marked increase in fibronectin within developing cleft regions. Similar to our work in the salivary gland, we found that blocking fibronectin inhibited branching.”

In blocking the protein from the organ cultures, however, the group found they could add purified fibronectin and progressively enhance the rate of branching. Previous reports in the biomedical literature indicate that two other molecules - TIMP-1 and epidermal growth factor - also can stimulate branching, but Sakai et al. found the effects of fibronectin to be “substantially greater.” In fact, the scientists said they succeeded in doubling the rate of branching.

Yamada said the Nature paper should be of interest to laboratories involved in tissue engineering, especially those engaged in studies to develop an artificial salivary gland. “In theory, you could have a bioengineered polymeric structure serve as the framework for the artificial gland,” he said. “But you would still have to use biological catalysts to trigger adequate three-dimensional structure. You would need to insert the tissue and induce it to fill up the framework with the appropriate amount of branching to generate enough surface area to produce adequate amounts of saliva. Our paper suggests a molecular mechanism that will be important in doing that.”

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This page last updated: February 26, 2014