Recent Progress in Understanding Salamander Regeneration

How is it that salamanders can regenerate major organs and limbs, while mammals cannot? There is some interest in this question in the medical community, for all the obvious reasons, although it remains unknown as to how challenging it will be to pick out specific elements in the biochemistry of another species and port them over to we humans. Any given case might be made to work with near-future biotechnology or might prove to be unfeasible for the foreseeable future, but we won't know until researchers make it 80% of the way to the final goal. Thus there is funding and enthusiasm in a range of laboratories for work on better understanding the essential differences in regeneration between salamanders and mammals, spurred on by incidental, unrelated discoveries such as a breed of mice capable of healing some wounds without scarring, or a better grasp of the rare cases in which human fingertips grow back.

Over the past decade a steady series of research results have increased knowledge of the mechanisms of salamander regeneration, both in terms of how different cell populations are behaving, and at the lower level of changes in protein levels, signaling pathways, and gene expression. Here is another piece of the puzzle, though it is clearly still a long way from here to a level of understanding that enables safe manipulation of mammalian cells via this mechanism to create greater feats of regeneration:

Salamanders give clues to how we might regrow human limbs

Although we do not yet understand the exact mechanisms by which salamanders are able to regrow their limbs, we do know that this animal regeneration takes place by the reprogramming of adult cells. This means that for regeneration to take place, adult cells - such as muscle cells - that form the limb have to lose their muscle identity and proliferate to give rise to new cells that will contribute to form the new structure. This process is rarely found in mammalian cells and this has been suggested as the basis for their poor regenerative abilities.

We recently found a critical component of the reprogramming mechanism. In our [study], we demonstrated that the sustained activation of a molecular pathway (a group of molecules in a cell that work together to control a particular function or functions) - called the ERK pathway - plays a key role during the natural reprogramming of salamander muscle cells. Only when the ERK pathway is constantly switched "on" are the cells able to re-enter the cell cycle, which is key to their regenerative potential.

We also compared salamander and mammalian muscle cells. In contrast to salamander cells, we found that mammalian cells can only activate the ERK pathway transiently, and fail to keep the pathway switched "on". Critically, we found that if we forced these mammalian cells to keep the ERK pathway activated (by giving them a piece of DNA that allows them to produce a protein that activates the pathway), the cells could produce the proteins involved in cell cycle re-entry. This suggests that the manipulation of the pathway could contribute to therapies to enhance the regenerative potential in humans.

Sustained ERK Activation Underlies Reprogramming in Regeneration-Competent Salamander Cells and Distinguishes Them from Their Mammalian Counterparts

In regeneration-competent vertebrates, such as salamanders, regeneration depends on the ability of various differentiated adult cell types to undergo natural reprogramming. This ability is rarely observed in regeneration-incompetent species such as mammals, providing an explanation for their poor regenerative potential. To date, little is known about the molecular mechanisms mediating natural reprogramming during regeneration. Here, we have identified the extent of extracellular signal-regulated kinase (ERK) activation as a key component of such mechanisms. We show that sustained ERK activation following serum induction is required for re-entry into the cell cycle of postmitotic salamander muscle cells, partially by promoting the downregulation of p53 activity.

Remarkably, while long-term ERK activation is found in salamander myotubes, only transient activation is seen in their mammalian counterparts, suggesting that the extent of ERK activation could underlie differences in regenerative competence between species.

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