A Limb Regeneration Mystery Solved

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Cell specific: This image shows a section of regenerated salamander limb. Fluorescently labeled Schwann cells (green) are wrapped around nerves (red). There is no fluorescence found in the other cells (blue), which shows that Schwann cells do not turn into other cell types during regeneration. Credit: D. Knapp/E. Tanaka

The researchers also found that some cells remember not only their identities but also their position in the body. Cartilage cells, for instance, remember if they are supposed to form an upper arm, lower arm, or hand, while Schwann cells simply migrate anyplace that they are needed.

Tanaka says that the finding will provoke a major shift in thinking about the requirements of regeneration. In explaining why salamanders can regrow limbs and humans can't, she says, "the hypothesis was that it's because salamanders can powerfully alter the identity of cells." But in fact, their cells never really lose their identities; instead, they seem to use tissue-specific stem cells capable of generating a certain part of the new limb. Tanaka points out that humans also have tissue-specific stem cells that replace different kinds of tissue. Perhaps salamanders "are not doing something much more complicated than what human stem cells would do," she says. Coaxing human cells to regenerate might not require steps as drastic as making cells pluripotent.

Alejandro Sánchez Alvarado, a scientist who studies regeneration at the University of Utah School of Medicine, says that this method of "tattooing" the transplanted cells genetically is "a novel technique for the field of regeneration." Tanaka believes that previous studies may have misled researchers by using imperfect tracking methods such as dyes by culturing cells before transplanting them and possibly altering them, or by allowing different cell types to contaminate samples.

Sánchezalso says that the idea that blastemas held several different cell types was a "minority hypothesis" and that this study "shows that this hypothesis turns out to be correct." He cautions that scientists now need to determine whether this phenomenon is the same in adult axolotls and in newts, which are a primary model organism for regeneration studies. But if the same mechanism turns out to underlie other cases of regeneration, it would change what scientists believe is required to regrow body parts, Sánchezsays. But it leaves a major question unanswered: if humans already have tissue-specific stem cells, what exactly is the difference between our cells and those of salamanders?