regeneration

Changing one gene can restore some tissue regeneration to mice

Regeneration is a trick many animals, including lizards, starfish, and octopuses, have mastered. Axolotls, a salamander species originating in Mexico, can regrow pretty much everything from severed limbs, to eyes and parts of brain, to the spinal cord. Mammals, though, have mostly lost this ability somewhere along their evolutionary path. Regeneration persisted, in a limited number of tissues, in just a few mammalian species like rabbits or goats.

“We were trying to learn how certain animals lost their regeneration capacity during evolution and then put back the responsible gene or pathway to reactivate the regeneration program,” says Wei Wang, a researcher at the National Institute of Biological Sciences in Beijing. Wang’s team has found one of those inactive regeneration genes, activated it, and brought back a limited regeneration ability to mice that did not have it before.

Of mice and bunnies

The idea Wang and his colleagues had was a comparative study of how the wound healing process works in regenerating and non-regenerating mammalian species. They chose rabbits as their regenerating mammals and mice as the non-regenerating species. As the reference organ, the team picked the ear pinna. “We wanted a relatively simple structure that was easy to observe and yet composed of many different cell types,” Wang says. The test involved punching holes in the ear pinna of rabbits and mice and tracking the wound-repairing process.

The healing process began in the same way in rabbits and mice. Within the first few days after the injury, a blastema—a mass of heterogeneous cells—formed at the wound site. “Both rabbits and mice will heal the wounds after a few days,” Wang explains. “But between the 10th and 15th day, you will see the major difference.” In this timeframe, the earhole in rabbits started to become smaller. There were outgrowths above the blastema—the animals were producing more tissue. In mice, on the other hand, the healing process halted completely, leaving a hole in the ear.

To regenerate a head, you first have to know where your tail is

Biology, planaria, regeneration, Science / Shannon Garcia / April 19, 2025

Before a critical point in development, the animals failed to close the wound made by the cut, causing the two embryo halves to simply spew cells out into the environment. Somewhat later, however, there was excellent survival, and the head portion of the embryo could regenerate a tail segment. This tells us that the normal signaling pathways present in the embryo are sufficient to drive the process forward.

But the tail of the embryo at this stage doesn’t appear to be capable of rebuilding its head. But the researchers found that they could inhibit wnt signaling in these posterior fragments, and that was enough to allow the head to develop.

Lacking muscle

One possibility here is that wnt signaling is widely active in the posterior of the embryo at this point, blocking formation of anterior structures. Alternatively, the researchers hypothesize that the problem is with the muscle cells that normally help organize the formation of a stem-cell-filled blastema, which is needed to kick off the regeneration process. Since the anterior end of the embryo develops earlier, they suggest there may simply not be enough muscle cells in the tail to kick off this process at early stages of development.

To test their hypothesis, they performed a somewhat unusual experiment. They started by cutting off the tails of embryos and saving them for 24 hours. At that point, they cut the front end off tails, creating a new wound to heal. At this point, regeneration proceeded as normal, and the tails grew a new head. This isn’t definitive evidence that muscle cells are what’s missing at early stages, but it does indicate that some key developmental step happens in the tail within the 24-hour window after the first cut.

The results reinforce the idea that regeneration of major body parts requires the re-establishment of the signals that lay out organization of the embryo in development—something that gets complicated if those signals are currently acting to organize the embryo. And it clearly shows that the cells needed to do this reorganization aren’t simply set aside early on in development but instead take some time to appear. All of that information will help clarify the bigger-picture question of how these animals manage such a complex regeneration process.

Current Biology, 2025. DOI: 10.1016/j.cub.2025.03.065 (About DOIs).

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