For the past 40 years, researchers have been trying to fully comprehend how salamanders regrow their limbs, tails and even retina. Harnessing that knowledge would help us pinpoint the differences between species, and would bring us closer to reactivate these regeneration mechanisms in mammals. Recently, a study made by Nacu and colleagues revealed important signaling mechanisms that orchestrate and promote limb regeneration in salamanders.

How Limb Regeneration Occurs

In salamanders, limb regeneration is characterized by a complex crosstalk between cells surrounding the initial injury site. Briefly, after limb amputation, wounding will trigger essential events for tissue growth. First, the wound is closed by the epidermis, forming a physical a barrier and preventing infections, like in mammals. However, in these amphibians, epidermal cells continue to migrate and accumulate over the initial wound site. In the next days, the cells present in the thickened tissue will de-differentiate, meaning they will go back to a “stem cell state”, and will proliferate to give rise to the blastema.

Recapping this embryonic development, this growing mass will coordinate important cell-to-cell signaling events that are responsible for the instructions that lead to neuronal innervations, blood vessel penetration and muscle growth. Within 1 to 3 months, depending on the age of the salamander, connections lost after wounding, and limb function, are reestablished.

Dissecting Cellular Crosstalk Necessary For Regeneration

To enable regeneration, the blastema needs innervations and needs to be composed of cells from both the anterior and posterior limb site. On the other hand, transplanting a patch of a posterior limb, on an anterior limb injury, can result in an extra (accessory) limb formation.

In this study, Nacu and colleagues clarified the molecular basis that leads to this supernumerary limb formation, and justified the need for anterior-posterior tissue interactions for complete limb formation. By activating hedgehog signaling, the signaling that sends information to embryonic cells, researchers were able to drive regeneration of an anterior blastema that would normally regress otherwise. Moreover, in blastemas containing only posterior tissue, the combination of the sonic hedgehog (SHH) protein and the expression of fibroblast growth factor 8 (FGF8) were sufficient for limb outgrowth.

In summary, this study dissects the important roles of SHH and FGF8 signaling pathways in the development of the blastema, and contributes to the progress in the quest to understand this amazing regenerating process. Scientists have learned quite a bit from the animal kingdom and, hopefully, this is one discovery that will help push regenerative medicine forward.

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