Discovery in Salamanders Could Lead to Human Limb Regeneration

By tracking individual cells in genetically modified salamanders, researchers have found an unexpected explanation for their seemingly magical ability to regrow lost limbs.

Rather than having their cellular clocks fully reset and reverting to an embryonic state, cells in the salamanders’ stumps became slightly less mature versions of the cells they’d been before. The findings could inspire research into human tissue regeneration.

“The cells don’t have to step as far back as we thought they had to, in order to regenerate a complicated thing like a limb,” said study co-author Elly Tanaka, a Max Planck Institute cell biologist. “There’s a higher chance that human or mammalian cells can be induced into doing the same thing.”

Integrative and comparitive biology journal – Evidence for the Local Evolution of Mechanisms Underlying Limb Regeneration in Salamanders

The most extensive regenerative ability in adult vertebrates is found in the salamanders. Although it is often suggested that regeneration is an ancestral property for vertebrates, our studies on the cell-surface three-finger-protein Prod 1 provide clear evidence for the importance of local evolution of limb regeneration in salamanders. Prod 1 is implicated in both patterning and growth in the regeneration of limbs. It interacts with well-conserved proteins such as the epidermal growth-factor receptor and the anterior gradient protein that are widely expressed in phylogeny. A detailed analysis of the structure and sequence of Prod 1 in relation to other vertebrate three-finger proteins in mammals and zebra fish supports the view that it is a salamander-specific protein. This is the first example of a taxon-specific protein that is clearly implicated in the mechanisms of regeneration. We propose the hypothesis that regeneration depends on the activity of taxon-specific components in orchestrating a cellular machinery that is extensively conserved between regenerating and non-regenerating taxa. This hypothesis has significant implications for our outlook on regeneration in vertebrates, as well as for the strategies employed in extending regenerative ability in mammals.

If Tanaka’s findings hold, they suggest a relatively new avenue for stem cell research. Bodies might find it easier to accept cells that have been only partially reprogrammed, like those in the axolotl’s blastema, than embryonic or fully reprogrammed cells.

“The salamanders are dialing the timeline back a few steps,” he said. “They don’t go all the way back and ask a cell to catch up,” said Sánchez Alvarado.

This approach has shown promise in the lab of Harvard Stem Cell Institute co-director Douglas Melton, who last year used partial reprogramming on pancreas cells that subsequently formed other pancreas cell types.

“This represents a parallel approach for how to make cells in regenerative medicine,” said Melton at the time. “If you’ve got extra cells of one type and need another, why go all the way back to a stem cell?”

Tanaka next hopes to decipher the genetic instructions governing blastema formation. But however the pluripotency–versus–partial-reprogramming debate turns out, her team’s development of a genetically modified axolotl as a model organism for regenerative research is significant.

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