Global-positioning system aficionados know that it's possible to precisely define any location in the world with just three geographic coordinates: latitude, longitude and altitude. Now scientists at the Stanford University School of Medicine have discovered that specialized skin cells use a similar mapping system to identify where they belong in the body and how to act once they arrive.
These cellular cornerstones direct embryonic patterning and wound healing by sending vital location cues to their neighbors, and may help in growing tissue for transplant or understanding metastatic cancer.
"There is a logic to the body that we didn't understand before," said John Rinn, PhD, a postdoctoral scholar in the laboratory of Howard Chang, MD, PhD, assistant professor of dermatology. "Our skin is actively maintaining itself throughout our life, and these 'address codes' help the cells know how to respond appropriately." Rinn is the first author of the research, which is published in the current issue of Public Library of Science-Genetics.
Until now it's been a mystery as to how adult skin, which consists of basically the same components all over the body, knows to grow hair in some areas like the scalp, while manufacturing sweat glands, calluses and fingerprint whorls in others. In 1969, well-known developmental biologist Lewis Wolpert authored a famous treatise that described two possible ways for cells to know where they are in the body: Either they infer their location and adjust their behavior based on interactions with nearby cells, or they deduce their "positional identity" through the use of some type of coordinate system. The findings from the new Stanford study bolster the second possibility.
The scientists analyzed the gene-expression profiles of adult fibroblasts from more than 40 areas of the body. They found about 400 genes whose expression patterns varied with the cells' original location. Those from the top half of the body - arms, head and chest, for example - shared expression patterns that were markedly different from the patterns shared among cells from the bottom part of the body, such as the legs and feet. Similar patterns existed among cells originating close to or far from the center of the body, and those from the outer or the inner layer of the skin.
While these three rough anatomical divisions don't provide the precise coordinates of a global-positioning system, they do help explain similarities between the skin on the palms of the hands and the relatively distant soles of the feet. Like botanically similar areas of the world that share a latitude and altitude but differ in longitude, both the palms and soles are on the outer layer of the skin far from the center of the body and are more like one another than like their biological neighbors.
"Ideally, we can use this finding to develop a positional map that will allow us to correlate location with function in a way that will make it easier to regenerate certain parts of the body," said Rinn. "For example, if we need to grow skin in the laboratory to graft onto someone with badly burned palms, we'll know how to turn on the specific genes that make that type of skin." The implications are vast. Fibroblasts and other skin cells also comprise the lining of the lung and intestine as well as internal organs.
Not every kind of skin cell expresses gene patterns that can be correlated with their location in the body; the study found no such association in endothelial cells, which might depend on signals from surrounding cells.
"It's not like every cell has this code," said Rinn. "I like to think of the fibroblasts as wise, old parental cells who may tell the others how to behave." Their input is invaluable during embryogenesis, normal growth and wound healing, each of which requires location-specific responses by cells. Many of the genes identified by Rinn are known to be important in patterning the early embryo.
Rinn and his colleagues speculate that some of these processes may require more specific location indicators than the three they've currently identified. It's possible that additional cues may be provided by variations in gene expression levels too subtle to be detected in their current study. Alternatively, cell types other than fibroblasts or endothelial cells may express signals that further refine the current rough map. Finally, it's possible that adults simply don't need the same level of precision mapping as a developing embryo, and they stop broadcasting the finer points of the signal when it's no longer necessary.
Rinn and Chang's Stanford colleagues who participated in the research include research assistant Chanda Bondre; Hayes B. Gladstone, MD, assistant professor of dermatology; and Patrick Brown, MD, PhD, professor of biochemistry. The research was funded by the Damon Runyon Cancer Foundation and the Howard Hughes Medical Institute.
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