Biologists Discover Secret To Salamander Limb Regeneration

axolotl, Mexican salamander
The axolotl or Mexican salamander (Ambystoma mexicanum); image credit : LoKiLeCh ; CC – BY – SA 3.0 Unported

Salamanders aren’t just cool looking, detritus-dwelling amphibians. Salamanders are wonders of nature; they have the remarkable ability to regenerate their limbs, tails and even their retinas, spinal cords and some parts of their hearts and brains. Even following “deep tissue” wounds, salamanders are able to achieve scar-free repair of these injuries. What’s more, this regenerative capacity is not limited to young salamanders — it is possible at any stage of the amphibian’s life-cycle.

But just how this miraculous-seeming, amphibian ability is made possible has remained mostly a mystery to scientists that study them. That is, until now.

A trio of experimental biologists (Godwin, Pinto, Rosenthal), publishing their work on-line via the Proceedings of the National Academy of Sciences, have convincingly revealed the key cellular and molecular features of the amphibian’s regenerative powers.

In adult mammals, damaged (severed) body parts are not replaced naturally with new parts. In some adult mammals, there is partial limb repair, but rarely complete regrowth (note: many young mammals can regrow their digits, if only partially). It is believed that this failure to regenerate is the result of a “muted growth response” and what’s known as fibrotic scarring (the scarring serves as a barrier to continued regrowth).

There is also an immune system role in mammalian wound repair. Scientists have suspected for awhile that some type of critical but unique immune response is at work in Salamander wound repair as well. However, the mechanisms involved in this response were incompletely understood.

The Details of Salamander Limb Regeneration

The researchers conducted a comprehensive analysis of immune cell signalling during limb regeneration by an aquatic salamander called an axolotl (Ambystoma mexicanum). Their analysis revealed a “temporally defined requirement for macrophage infiltration in the regenerative process.” [source: see link below].

Macrophages (“large eaters”) are a key class of immune cells (leukocytes) that are integrally involved in what’s known as the “pro-inflammatory response” that accompanies injury, infection, and physical stress.They also secrete chemokines and cytokines — immune signalling molecules that tell other types of immune cells to “come here now!” Apart from this crucial signalling role, macrophages also clear dead cells from the site of injury and also produce factors which (at a later point) suppress the inflammatory response and promote fibroblast migration, angiogenesis (blood vessel formation), collagen remodeling, and cell replication.

Now, both mammals and amphibians have these immune cells, but in salamanders, they are “more dynamically deployed” and induce both inflammatory and anti-inflammatory signals simultaneously — all within 24 hours following limb amputation (yes, their limbs were amputated, but not permanently). This rapid response is key to the salamander’s regenerative ability; in mammals, macrophages typically arrive at wound sites 48–96 hours after injury

To demonstrate that this “temporarily defined” macrophage activity was indeed the key to limb regeneration, the team systematically depleted macrophages prior to amputating the amphibians. The result was wound closure but “permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression.” This is pretty much what one would expect in an adult mammal experiencing the same injury.

However, and most importantly, the failed, limb “stumps” were fully restored upon replenishment of the endogenous macrophage population and the reamputation of the stumps.

The team believes that limb regeneration occurs in a “regeneration-permissive environment” which is promoted and enabled by these macrophage-derived therapeutic molecules.

The work will likely provide a solid basis of clinical applications for the regeneration of damaged body parts in adult mammals (that would include humans, of course).

The results are published in the (free PDF) paper: ‘Macrophages are required for adult salamander limb regeneration’ (PNAS 2013 ; published ahead of print May 20, 2013, doi:10.1073/pnas.1300290110)

About the Axolotl Salamander

The axolotl (a Nāhuatl āxōlōtl (singular) or āxōlōmeh (plural) word meaning “water monster”), or Mexican salamander (Ambystoma mexicanum), is a neotenic salamander (meaning it retains attributes of youth through adulthood), as the larvae fail to undergo metamorphosis and adults remain aquatic and retain their gills.The species originates from lakes including Lake Xochimilco that underlies Mexico City. The axolotl is a close relative of the tiger salamander (Ambystoma tigrinum).

In recent years (as of 2010) wild axolotls have become nearly extinct due to pollution and habitat destruction (primarily through urbanization around Mexico
city). Also, invasive species such as the African tilapia and the Asian carp tend to eat the amphibian’s young and also compete over their primary food source.

The salamander’s survival is currently assured due to its value as an experimental animal model in tissue regeneration studies.

The axolotl is currently on the International Union for Conservation of Nature’s annual Red List of threatened species. nearly a third of the world’s amphibians (including frogs, toads, salamanders, a caecilians) are either going extinct or are functionally extinct in the wild due to a confluence of lethal factors.



About the Author

Michael Ricciardi is a well-published writer of science/nature/technology articles as well as essays, poetry and short fiction. Michael has interviewed dozen of scientists from many scientific fields, including Brain Greene, Paul Steinhardt, Arthur Shapiro, and Nobel Laureate Ilya Progogine (deceased). Michael was trained as a naturalist and taught natural science on Cape Cod, Mass. from 1986-1991. His first arts grant was for production of the environmental (video) documentary 'The Jones River - A Natural History', 1987-88 (Kingston, Mass.). Michael is an award winning, internationally screened video artist. Two of his more recent short videos; 'A Time of Water Bountiful' and 'My Name is HAM' (an "imagined memoir" about the first chimp in space), and several other short videos, can be viewed on his website ( He is also the author of the ebook 'Zombies, E.T's, and The Super Entity - A Selection of Most Stimulating Articles' and for Kindle: Artful Survival ~ Creative Options for Chaotic Times