Regeneration starts with a wound: Researchers demonstrate with flatworms and zebrafish that any injury can initiate regeneration of whole tissues

Some animals are naturally capable of something that remains merely an aspiration for humans - restoring lost body parts. In order to understand the mechanisms behind regenerative programs, researchers are studying such animals and have observed two types of healing processes. Some wounds, for example a scratch in the skin, resolve by wound healing. However, when pieces of tissue, or even whole limbs, are lost, the organism initiates complicated processes to restore the missing part of the body in its entirety. Previously, it was widely assumed that signals for complete regeneration were only activated when tissue was actually missing. Surprisingly, researchers from Münster and Ulm have now discovered that, in flatworms and zebrafish, all types of wounds trigger signals that can initiate the formation of whole tissues, such as heads in planarians and bones in fish. Both of these highly regenerative animals started the regenerative programme in response to every injury, regardless of severity. However, regeneration only continued whenever tissue was missing. The researchers identified a cellular signalling pathway that informs the animals about whether tissue has been lost. “Our study raises the possibility that the wound healing response common to many animals, and potentially humans, could be redirected to regenerative outcomes,” says Dr. Kerstin Bartscherer, who is a team leader both at the Cells-in-Motion Cluster of Excellence at the University of Münster and at the Max Planck Institute for Molecular Biomedicine in Münster. “Providing wounded areas with the appropriate missing-tissue signals,” she says, “might therefore be a promising avenue for regenerative medicine.” The study has been published in “Nature Communications”.

The detailed story:

Planarian flatworms are of great interest to regenerative biologists because they have the unique ability to restore any part of their body - even the brain - in less than two weeks. Among vertebrates, the zebrafish is able to replace various severely damaged tissues and organs, including the heart and the tail fin. All animals with regenerative abilities must decide whether it is necessary to activate a regeneration response. “A long-standing fundamental question in the field is how these animals ‘know’ when to regenerate,” says lead author Dr. Suthira Owlarn, a biologist in Kerstin Bartscherer’s team.

In order to find out whether different wounds emit different signals, the researchers developed a new assay with which this question could be answered. They first manipulated the ability of flatworms to initiate the regeneration programme by inhibiting the activation of Extracellular Regulated Kinase (ERK). This enzyme mediates an important signalling pathway, which regulates various cellular processes, including regeneration initiation as they found in their study: after amputation of the heads of flatworms, the wound healed but no new tissues were formed - so these animals remained headless. Strikingly, when the researchers amputated tissue from these fragments again, the ERK pathway was re-activated and the fragments regenerated their missing head. Surprisingly, when the researchers made incisions, which normally lead to a healing rather than a regeneration response, these injuries also triggered head regeneration. “This shows that both wound types have regeneration-inducing power,” says Suthira Owlarn. “It also means all injuries can start the regeneration programme, but the programme is only completed if the injury is in an area where tissue is missing.”

In order to test whether these results can also be transferred to other living organisms, the team worked together with researchers around Prof. Gilbert Weidinger at the University of Ulm, who carried out similar experiments on zebrafish. The researchers made genetic modifications to the fish by ‘switching off’ their ability to initiate regeneration. The consequence, as with the flatworms, was that after the researchers had amputated the fishes’ fins, they healed the wound but failed to regenerate their fins and remained finless. They then inflicted simple skin injuries that do not normally induce regeneration and found that these injuries were able to trigger complete restoration in the fin fragments, including the bones. This confirmed what the researchers had found in planarians: regeneration is started generically after all wounds but the process is only completed when tissue is missing.

How does an animal know whether tissue is missing? To find that out, the researchers directed their attention to the beta-catenin protein, an activator of the Wnt signalling pathway. It has previously been shown that without this protein, animals erroneously form heads at all amputation sites. In the current work, the researchers now show that simple incisions made flatworms with altered Wnt signaling mistakenly grow heads at these injury sites. “This signalling pathway is therefore likely responsible for communicating tissue absence,” says Kerstin Bartscherer.

Whether the results of this basic research will lead to any potential applications cannot be predicted at the present time.

The study received funding from the Max Planck Society, the German Research Foundation and the European Research Council.

Original publication:

Owlarn S, Klenner F, Schmidt D, Rabert F, Tomasso A, Reuter H, Mulaw MA, Moritz S, Gentile L, Weidinger G, Bartscherer K. Generic wound signals initiate regeneration in missing-tissue contexts. Nat Commun 2017;8: 2282; DOI: 10.1038/s41467-017-02338-x.