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March 3, 2005

Tales of transdetermination: Tiny flies aid study of non-embryonic stem cells

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It has long been thought that cells that regenerate tissue do so by regressing to a developmentally younger state. Now two UW researchers have demonstrated that cells can regenerate without becoming “younger.”

Biologists for years have studied stem cells — the ones responsible for replenishing and regenerating an organism’s structures — aiming to find the means to selectively regenerate tissue such as that of the heart or liver in much the same way that the body heals a broken leg.

Much hope rests with non-embryonic stem cells, which can renew themselves and, within limits, produce all the specialized cell types from the type of tissue in which they originate. But scientists have puzzled over just how such cells function, how they can be spurred to create new tissue, and just when in their development it is determined what tissue they can produce.

Gerold Schubiger, a UW biology professor, and Anne Sustar, a research technician in his laboratory, used groups of cells, called imaginal discs, in fruit fly larvae to provide an easily controlled system to study regeneration. Imaginal discs convert genetic information that determines the specific tissue into which the cells will develop in the adult fly. For example, leg discs form only adult legs and wing discs form only adult wings. Normally, all of those cells develop into that specific tissue, either when the fly reaches the adult stage or when regenerating a lost structure, such as parts of a leg disc.

The exception is a very small number of cells in each disc, located at what the researchers term the “weak point.” These cells change their ultimate destiny, or fate, as the disc regenerates tissue so that, for example, instead of regenerating leg structures they form wing structures. Such fate changes are known as transdetermination, and they demonstrate that a few cells have development potential that is adaptable rather than firmly fixed, Schubiger said. That has parallels in the adaptable development potential found in some vertebrate stem cells, he said.

In the case of the fruit flies, regeneration and transdetermination begin in the “weak point” of the leg imaginal disc when a signaling gene called wingless activates a selector gene called vestigial, which spurs wing development in that stem cell-like region.

“In all organisms, selector genes activate or repress other genes that trigger production of different organs. Researchers studying cells with adaptable development potential want to know when, where and how those cells change their fate,” Schubiger said.

In previous research involving vertebrates, he said, it was unclear whether cells involved in tissue regeneration had reverted to a younger state or were the same age as other cells in the organism. But he noted that it has been generally accepted that the regenerating cells revert to a younger state.

If that is true, those cells would have to divide faster than the others in the organism because younger cells divide faster than older cells. Sustar and Schubiger tested the theory in fruit flies, following the cells to see when and where the vestigial gene was activated. Since cells in the disc divide more slowly as they age, the researchers could see whether the cells involved in regeneration had reverted to a younger cycle. They found that neither cells involved in regeneration nor those that were changing their fate to become a different type of tissue had the characteristics, including the faster doubling time, of younger cells.

Sustar is the lead author of a paper describing the work, published in the Feb. 11 edition of the journal Cell. The work was supported by a grant from the National Institutes of Health.

Understanding the wingless gene’s function is key to understanding how stem cells can adapt their ultimate destiny, from leg tissue to wing tissue for example, Schubiger said.

There are many examples in which the wingless gene causes stem cells to change fates, he added. In hair follicle cells, for example, the wingless gene changes stem cells to skin cells. In a mouse, high levels of wingless genes change a specific group of lung cells into intestine cells.

“This work challenges old concepts of regeneration and has opened new avenues for stem cell research,” Schubiger said. “This remarkable observation has not been reported in any stem cell research. We have set the stage to look at the cell cycle in other stem cell systems.”